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[1.] Analyse:Asa/Fragment 010 03 - Diskussion
Bearbeitet: 14. August 2014, 13:02 Graf Isolan
Erstellt: 14. August 2014, 12:06 (Graf Isolan)
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1. Introduction:

The immune system has two major components, an innate arm and an adaptive arm. The innate immune system is a universal and ancient form of host defense against infection. Innate immune system recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved metabolites produced by pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Innate immunity covers many areas of host defense against pathogenic microbes, including the recognition of pathogen-associated molecular patterns (PAMPs) (Janeway, 1989). In contrast, the adaptive immune system involves great variability and rearrangement of receptor gene segments to generate receptors, which yield myriad of antibodies or T cell receptors (TcRs) of exquisite specificity for each of potential antigens, additionally the adaptive immune system is characterized by immunological memory. However, the adaptive immune response is also responsible for allergy, autoimmunity, and the rejection of allograft.


Janeway, C.A., Jr. (1989). Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54 Pt 1, 1-13.

[Page 197]

Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. [...]

[...]

Innate immunity covers many areas of host defense against pathogenic microbes, including the recognition of pathogen-associated molecular patterns (PAMPs) (1). [...]

[...] Because the mechanism of generating receptors in the adaptive immune system involves great variability and rearrangement of receptor gene segments, the adaptive immune system can provide specific recognition of foreign antigens, immunological memory of infection,

[Page 198]

and pathogen-specific adaptor proteins. However, the adaptive immune response is also responsible for allergy, autoimmunity, and the rejection of tissue grafts.


1. Janeway CA Jr. 1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp. Quant. Biol. 54:1–13

Anmerkungen

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[2.] Analyse:Asa/Fragment 010 24 - Diskussion
Bearbeitet: 14. August 2014, 13:24 Graf Isolan
Erstellt: 14. August 2014, 13:19 (Graf Isolan)
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The innate immune system is made of many cell types, such as macrophages, dendritic cells (DCs), mast cells, neutrophils, eosinophils and NK cells. These cells can become activated during an inflammatory response, which is a consistent sign of infection with a pathogenic microbe. Such cells rapidly differentiate into short-lived effector cells whose main role is to get rid of the infection. However, in certain cases, the innate immune system is unable to deal with the infection, and activation of an adaptive immune response becomes necessary. In these cases, the innate immune system can instruct the adaptive immune system about the nature [of the pathogenic challenge.] [Page 199]

The innate immune system is made of many cells, such as those white blood cells that are not B lymphocytes or T lymphocytes of the adaptive immune system. [...]

[...]

Among the cells that bear innate immune or germline-encoded recognition receptors are macrophages, dendritic cells (DCs), mast cells, neutrophils, eosinophils, and the so-called NK cells. These cells can become activated during an inflammatory response, which is virtually always a sign of infection with a pathogenic microbe. Such cells rapidly differentiate into short-lived effector cells whose main role is to get rid of the infection; in this they mainly succeed without recourse to adaptive immunity. However, in certain cases, the innate immune system is unable to deal with the infection, and so activation of an adaptive immune response becomes necessary. In these cases, the innate immune system can instruct the adaptive immune system about the nature of the pathogenic challenge.

Anmerkungen

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[3.] Analyse:Asa/Fragment 011 01 - Diskussion
Bearbeitet: 14. August 2014, 17:54 Graf Isolan
Erstellt: 14. August 2014, 16:49 (Graf Isolan)
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It does so through cytokines and chemokines and the expression of costimulatory molecules, such as CD80 and CD86, on the surface of specialized antigen-presenting cells (APCs), with DCs as the most important ones that alarm from infection in virtually all tissues (Banchereau and Steinman, 1998; Fearon and Locksley, 1996; Janeway, 1989).

Banchereau, J., and Steinman, R.M. (1998). Dendritic cells and the control of immunity. Nature 392, 245-252.

Fearon, D.T., and Locksley, R.M. (1996). The instructive role of innate immunity in the acquired immune response. Science 272, 50-53.

Janeway, C.A., Jr. (1989). Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54 Pt 1, 1-13.

It does so through the expression of costimulatory molecules, such as CD80 and CD86, on the surface of specialized antigen-presenting cells, the most important of which are the dendritic cells that guard against infection in virtually all tissues (1, 3, 4).

1. Janeway CA Jr. 1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp. Quant. Biol. 54:1–13

3. Fearon DT, Locksley RM. 1996. The instructive role of innate immunity in the acquired immune response. Science 272:50–53

4. Banchereau J, Steinman RM. 1998. Dendritic cells and the control of immunity. Nature 392:245–52

Anmerkungen

Continues from Asa/Fragment_010_24. Not marked as a citation. Taken verbatim including the references.

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[4.] Analyse:Asa/Fragment 011 24 - Diskussion
Bearbeitet: 9. October 2014, 00:13 Graf Isolan
Erstellt: 14. August 2014, 20:15 (Graf Isolan)
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Both classes of MHC molecules are heterodimers with similar architectures and are composed of three domains, one α-helix/β-sheet superdomain that forms the peptide-binding site and two immunoglobulin (Ig)-like domains (Fig.1) (Bjorkman et al., 1987b; Brown et al., 1993; Fremont et al., 1996; Madden et al., 1993; Matsumura et al., 1992; Stern and Wiley, 1994). The overall architecture is the same in both MHC classes, where a seven-[stranded β-sheet represents the floor of the peptide-binding groove, and the sides are formed by two long α-helices, that straddle the β-sheet.]

Bjorkman, P.J., Saper, M.A., Samraoui, B., Bennett, W.S., Strominger, J.L., and Wiley, D.C. (1987b). Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506-512.

Brown, J.H., Jardetzky, T.S., Gorga, J.C., Stern, L.J., Urban, R.G., Strominger, J.L., and Wiley, D.C. (1993). Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364, 33-39.

Fremont, D.H., Hendrickson, W.A., Marrack, P., and Kappler, J. (1996). Structures of an MHC class II molecule with covalently bound single peptides. Science 272, 1001-1004.

Madden, D.R., Garboczi, D.N., and Wiley, D.C. (1993). The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell 75, 693-708.

Matsumura, M., Fremont, D.H., Peterson, P.A., and Wilson, I.A. (1992). Emerging principles for the recognition of peptide antigens by MHC class I molecules. Science 257, 927-934.

Stern, L.J., and Wiley, D.C. (1994). Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2, 245-251.

Both classes of MHC are heterodimers with similar architectures and are composed of three domains, one α-helix/β-sheet (αβ) superdomain that forms the peptide-binding site and two Ig-like domains. [...] Notwithstanding, in both MHC classes, the overall architecture is the same where a seven-stranded β-sheet represents the floor of the binding groove, and the sides are formed by two long α-helices (or continuous α-helical segments in the α2- or β1-helices) that straddle the [β-sheet (Figure 2a,b).]

43. Madden DR, Garboczi DN, Wiley DC. 1993. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLAA2. Cell 75:693–708

44. Stern LJ,Wiley DC. 1994. Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2:245–51

Anmerkungen

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[5.] Analyse:Asa/Fragment 012 01 - Diskussion
Bearbeitet: 9. October 2014, 00:13 Graf Isolan
Erstellt: 14. August 2014, 20:53 (Graf Isolan)
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[The overall architecture is the same in both MHC classes, where a seven-]stranded β-sheet represents the floor of the peptide-binding groove, and the sides are formed by two long α-helices, that straddle the β-sheet.

In MHC class I molecules, the peptide-binding site is constructed from the heavy chain only, and an additional 12-kDa light chain subunit, β2-microglobulin (β2m), associates with the α3 domain of the heavy chain (Fig.1).

[Page 420]

In class I MHC molecules, the peptide-binding site (called the α1α2 domain) is constructed from the heavy chain only, and an additional light chain subunit, β2-microglobulin (β2m), associates with α3 of the heavy chain. In contrast, the class II MHC peptide-binding site is assembled from two heavy chains (α1β1). Notwithstanding, in both MHC classes, the overall architecture is the same where a seven-stranded β-sheet represents the floor of the binding groove, and the sides are formed by two long α-helices (or continuous α-helical segments in the α2- or β1-helices) that straddle the

[Page 421]

β-sheet (Figure 2a,b).

Anmerkungen

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(Graf Isolan)

[6.] Analyse:Asa/Fragment 012 27 - Diskussion
Bearbeitet: 9. October 2014, 00:13 Graf Isolan
Erstellt: 15. August 2014, 13:16 (Graf Isolan)
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The groove is generally long enough to accommodate 8 or 9 residues in an extended conformation (Madden et al., 1991) with the termini and the so-called anchor residues buried in specificity pockets that differ from allele to allele (Fremont et al., 1992; Madden et al., 1993). This binding mode leaves the upward-pointing peptide side chains available for direct interaction with the TcR. Longer peptides can either [bind by extension at the C terminus (Stern et al., 1994) or due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TcR recognition (Speir et al., 2001; Tynan et al., 2005).]

Fremont, D.H., Matsumura, M., Stura, E.A., Peterson, P.A., and Wilson, I.A. (1992). Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science 257, 919-927.

Madden, D.R., Gorga, J.C., Strominger, J.L., and Wiley, D.C. (1991). The structure of HLAB27 reveals nonamer self-peptides bound in an extended conformation. Nature 353, 321-325.

Madden, D.R., Garboczi, D.N., and Wiley, D.C. (1993). The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell 75, 693-708.

Speir, J.A., Stevens, J., Joly, E., Butcher, G.W., and Wilson, I.A. (2001). Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. Immunity 14, 81-92.

Stern, L.J., and Wiley, D.C. (1994). Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2, 245-251.

Tynan, F.E., Burrows, S.R., Buckle, A.M., Clements, C.S., Borg, N.A., Miles, J.J., Beddoe, T., Whisstock, J.C., Wilce, M.C., Silins, S.L., et al. (2005). T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nat Immunol 6, 1114-1122.

Class I MHC molecules usually bind peptides of 8–10 residues length (on average 9-mers, P1–P9) (Figure 3) in an extended conformation with the termini and the so-called anchor residues buried in specificity pockets that differ from allele to allele (42, 43). This binding mode leaves the upward-pointing peptide side chains available for direct interaction with the TCR (Figure 3). Longer peptides can either bind by extension at the C terminus (44) or, due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TCR recognition (22, 45).

22. Tynan FE, Borg NA, Miles JJ, Beddoe T, El-Hassen D, et al. 2005. High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I. Implications for T-cell receptor engagement and T-cell immunodominance. J. Biol. Chem. 280:23900–9

42. Fremont DH, Matsumura M, Stura EA, Peterson PA, Wilson IA. 1992. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science 257:919–27

43. Madden DR, Garboczi DN, Wiley DC. 1993. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLAA2. Cell 75:693–708

44. Stern LJ, Wiley DC. 1994. Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2:245–51

45. Speir JA, Stevens J, Joly E, Butcher GW, Wilson IA. 2001. Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. Immunity 14:81–92

Anmerkungen

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[7.] Analyse:Asa/Fragment 013 01 - Diskussion
Bearbeitet: 9. October 2014, 00:12 Graf Isolan
Erstellt: 15. August 2014, 15:16 (Graf Isolan)
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[Longer peptides can either] bind by extension at the C terminus (Stern et al., 1994) or due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TcR recognition (Speir et al., 2001; Tynan et al., 2005).

[Figure 1: Architecture of MHC-like molecules

(a) Class I molecules consist of a heavy chain (blue) and a light β2m chain (orange). The peptide-binding site is formed exclusively by elements of the heavy chain (b) Class II molecules; the peptide-binding site is assembled of both subunits. (Rudolph et. al. 2006)

[...] ]

In contrast, the MHC class II molecule are assembled from two heavy chains (αβ) in which the peptide-binding groove is open at either end, and the peptide termini are not fixed so that bound peptides are usually significantly longer than in MHC class I (Fig.1). The MHC class II allows presentation of peptides of 13-18 residues. The peptide backbone in MHC class II is confined mainly to a poly-proline type II conformation (Stern et al., 1994) and resides slightly deeper in the binding groove. Thus, the bound peptide is more accessible for TcR inspection in MHC class I due to its ability to bulge out of the groove, even for 9-mer peptides, however, in MHC class II the termini particularly the N-terminal extension, can play a major role in the TcR interaction.


Speir, J.A., Stevens, J., Joly, E., Butcher, G.W., and Wilson, I.A. (2001). Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. Immunity 14, 81-92.

Rudolph, M.G., Stanfield, R.L., and Wilson, I.A. (2006). How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol 24, 419-466.

Stern, L.J., and Wiley, D.C. (1994). Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2, 245-251.

Tynan, F.E., Burrows, S.R., Buckle, A.M., Clements, C.S., Borg, N.A., Miles, J.J., Beddoe, T., Whisstock, J.C., Wilce, M.C., Silins, S.L., et al. (2005). T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nat Immunol 6, 1114-1122.

[Page 420]

In contrast, the class II MHC peptide-binding site is assembled from two heavy chains (α1β1).

[Page 421]

Longer peptides can either bind by extension at the C terminus (44) or, due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TCR recognition (22, 45). In class II MHC, the groove is open at either end, and the peptide termini are not fixed so that bound peptides are usually significantly longer than in MHC class I (Figure 3). The peptide backbone in class II MHC is confined mainly to a poly-proline type II conformation (44) and resides slightly deeper in the binding groove. Thus, the bound peptide (P1–P9) is more accessible for TCR inspection in MHC class I due to its ability to bulge out of the groove, even for

[Page 423]

[Figure 2

Architecture of MHC-like molecules. The top panel shows the domain organization of the MHC(-like) molecules and the lower panel focuses on the ligand and/or receptor binding sites. (a) Class I molecules consist of a heavy chain (blue) and a light β2m chain (orange). The peptide-binding site is formed exclusively by elements of the heavy chain, whereas in class II molecules (b), it is assembled from both subunits. ]

9-mer peptides; however, in MHC class II, the termini, particularly the N-terminal extension (P-4 to P-1), can play a major role in the TCR interaction.


22. Tynan FE, Borg NA, Miles JJ, Beddoe T, El-Hassen D, et al. 2005. High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I. Implications for T-cell receptor engagement and T-cell immunodominance. J. Biol. Chem. 280:23900–9

44. Stern LJ, Wiley DC. 1994. Antigenic peptide binding by class I and class II histocompatibility proteins. Structure 2:245–51

45. Speir JA, Stevens J, Joly E, Butcher GW, Wilson IA. 2001. Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. Immunity 14:81–92

Anmerkungen

Not marked as a citation. Source is given only with regard to the figure.

Sichter
(Graf Isolan)

[8.] Analyse:Asa/Fragment 015 01 - Diskussion
Bearbeitet: 9. October 2014, 00:12 Graf Isolan
Erstellt: 16. August 2014, 15:33 (Graf Isolan)
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1.1.1.2 The T cell receptor

TcRs are cell surface heterodimers consisting of either disulfide-linked α and β or γ and δ -chains (Brenner et al., 1986; Chien et al., 1987; Hedrick et al., 1984; Koning et al., 1987; Saito et al., 1984; Winoto and Baltimore, 1989; Yanagi et al., 1984). Sequence analyses correctly predicted that TcRs would share a domain organization and binding mode similar to those of antibody Fab fragments (Davis and Bjorkman, 1988).


Brenner, M.B., McLean, J., Dialynas, D.P., Strominger, J.L., Smith, J.A., Owen, F.L., Seidman, J.G., Ip, S., Rosen, F., and Krangel, M.S. (1986). Identification of a putative second T-cell receptor. Nature 322, 145-149.

Chien, Y.H., Iwashima, M., Wettstein, D.A., Kaplan, K.B., Elliott, J.F., Born, W., and Davis, M.M. (1987). T-cell receptor delta gene rearrangements in early thymocytes. Nature 330, 722-727.

Davis, M.M., and Bjorkman, P.J. (1988). T-cell antigen receptor genes and T-cell recognition. Nature 334, 395-402.

Hedrick, S.M., Cohen, D.I., Nielsen, E.A., and Davis, M.M. (1984). Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149-153.

Koning, F., Stingl, G., Yokoyama, W.M., Yamada, H., Maloy, W.L., Tschachler, E., Shevach, E.M., and Coligan, J.E. (1987). Identification of a T3-associated gamma delta T cell receptor on Thy-1+ dendritic epidermal Cell lines. Science 236, 834-837.

Saito, H., Kranz, D.M., Takagaki, Y., Hayday, A.C., Eisen, H.N., and Tonegawa, S. (1984). A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature 312, 36-40.

Winoto, A., and Baltimore, D. (1989). Separate lineages of T cells expressing the alpha beta and gamma delta receptors. Nature 338, 430-432.

Yanagi, Y., Yoshikai, Y., Leggett, K., Clark, S.P., Aleksander, I., and Mak, T.W. (1984). A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145-149.

αβ and γδ TCRs

TCRs are cell surface heterodimers consisting of either disulfide-linked α- and β- or γ- and δ-chains. Sequence analyses correctly predicted that TCRs would share a domain organization and binding mode similar to those of antibody Fab fragments (69, 70).


69. Claverie JM, Prochnicka-Chalufour A, Bougueleret L. 1989. Implications of a Fab-like structure for the T-cell receptor. Immunol. Today 10:10–14

70. Davis MM, Bjorkman PJ. 1988. T-cell antigen receptor genes and T-cell recognition. Nature 334:395–402

Anmerkungen

Not marked as a citation.

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(Graf Isolan)

[9.] Analyse:Asa/Fragment 015 21 - Diskussion
Bearbeitet: 9. October 2014, 00:12 Graf Isolan
Erstellt: 16. August 2014, 16:21 (Graf Isolan)
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The first crystal structures of TcRs with MHC class I molecules led to proposals that the TcR orientation is approximately diagonal with a mean around 35° (Rudolph and Wilson, 2002). By contrast, in the first MHC class II complexes, the orientation was described as being closer to 90° (Hennecke et al., 2000; Reinherz et al., 1999) suggesting a different binding mode between the MHC classes (Wang and Reinherz, 2002).

Insight into the structural changes that supplement TcR-pMHC engagement must include crystal structures of the same TcR in its free and bound forms or of the same TcR bound to different pMHCs. Until recently, only two well-studied systems, the 2C and A6 TcRs, fullfilled these requirements. The 2C system allowed comparison of the free 2C TcR (Garcia et al., 1996a) with an agonist (Garcia et al., 1998) and a superagonist peptide (Degano et al., 2000) in complex with the same H-2Kb MHC.


Degano, M., Garcia, K.C., Apostolopoulos, V., Rudolph, M.G., Teyton, L., and Wilson, I.A. (2000). A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 12, 251-261.

Garcia, K.C., Degano, M., Pease, L.R., Huang, M., Peterson, P.A., Teyton, L., and Wilson, I.A. (1998). Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279, 1166-1172.

Garcia, K.C., Degano, M., Stanfield, R.L., Brunmark, A., Jackson, M.R., Peterson, P.A., Teyton, L., and Wilson, I.A. (1996a). An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 274, 209-219.

Hennecke, J., Carfi, A., and Wiley, D.C. (2000). Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLADR1. EMBO J 19, 5611-5624.

Reinherz, E.L., Tan, K., Tang, L., Kern, P., Liu, J., Xiong, Y., Hussey, R.E., Smolyar, A., Hare, B., Zhang, R., et al. (1999). The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286, 1913-1921.

Rudolph, M.G., and Wilson, I.A. (2002). The specificity of TCR/pMHC interaction. Curr Opin Immunol 14, 52-65.

Wang, J.H., and Reinherz, E.L. (2002). Structural basis of T cell recognition of peptides bound to MHC molecules. Mol Immunol 38, 1039-1049.

[Seite 432]

The first crystal structures of TCRs with class I molecules led to proposals that the TCR orientation is approximately diagonal with a mean around 35◦ (36). By contrast, in the first class II complexes, the orientation was described as being closer to perpendicular (15, 18), suggesting a different binding mode between the MHC classes (81).

[Seite 437]

Insight into the structural changes that accompany TCR/antigen engagement (i.e., induced fit) must include crystal structures of the same TCR in its free and bound forms or of the same TCR bound to different pMHCs. Until recently, only two well-studied systems, the 2C and A6 TCRs, fulfilled these requirements. The 2C system allowed comparison of the free 2C TCR (7) with an agonist (12) and a superagonist peptide (17) in complex with the same H-2Kb MHC (Figure 7a).


7. Garcia KC, Degano M, Stanfield RL, Brunmark A, Jackson MR, et al. 1996. An αβ T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 274:209–19

12. Garcia KC, Degano M, Pease LR, Huang M, Peterson PA, et al. 1998. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279:1166–72

15. Reinherz EL, Tan K, Tang L, Kern P, Liu J, et al. 1999. The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286:1913–21

17. Degano M, Garcia KC, Apostolopoulos V, Rudolph MG, Teyton L, Wilson IA. 2000. A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 12:251–61

18. Hennecke J, Carfi A, Wiley DC. 2000. Structure of a covalently stabilized complex of a human αβT-cell receptor, influenzaHApeptide andMHCclass II molecule, HLA-DR1. EMBO J. 19:5611–24

36. Rudolph MG,Wilson IA. 2002. The specificity of TCR/pMHC interaction. Curr. Opin. Immunol. 14:52–65

81. Wang JH, Reinherz EL. 2002. Structural basis of T cell recognition of peptides bound to MHC molecules. Mol. Immunol. 38:1039–49

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[This comparison disclosed a] functional hotspot between the CDR3 loops in the 2C TcR that finely discriminated between side chains and conformations of centrally located peptide residues through increased complementarity and additional hydrogen bonds. In the A6 system, altered peptide ligands (APLs) induced only subtle conformational changes in the TcR. In both the 2C and A6 systems, conformational changes are restricted mainly to the CDR3 loop regions, and the largest conformational differences were observed when comparing free versus bound TcRs (Rudolph and Wilson, 2002).

Rudolph, M.G., and Wilson, I.A. (2002). The specificity of TCR/pMHC interaction. Curr Opin Immunol 14, 52-65.

This comparison disclosed a functional hotspot between the CDR3 loops in the 2C TCR that finely discriminated between side chains and conformations of centrally located peptide residues through increased complementarity and additional hydrogen bonds. In the A6 system (13, 14), altered peptide ligands (APLs), i.e., peptides of slightly different sequence than the natural ligand, induced only subtle conformational changes in the TCR (Figure 7b). In both the 2C and A6 systems, conformational changes are restricted mainly to the CDR3 loop regions, and the largest conformational differences were observed when comparing free versus bound TCR (36).

13. Ding YH, Smith KJ, Garboczi DN, Utz U, Biddison WE,Wiley DC. 1998. Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Immunity 8:403–11

14. Ding YH, Baker BM, Garboczi DN, Biddison WE, Wiley DC. 1999. Four A6-TCR/peptide/HLA-A2 structures that generate very different T cell signals are nearly identical. Immunity 11:45–56

36. Rudolph MG,Wilson IA. 2002. The specificity of TCR/pMHC interaction. Curr. Opin. Immunol. 14:52–65

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Compared with αβ TcRs, much less is known about γδ TcRs (Fig.2). The biological function of the γδ TcRs is also ill defined. γδ T cells appear to respond to bacterial and parasitic infections (Morita et al., 1995) and primarily recognize phosphate-containing antigens (phosphoantigens) from mycobacteria by an unknown mechanism (Belmant et al., 1999; Morita et al., 1995).

Belmant, C., Espinosa, E., Poupot, R., Peyrat, M.A., Guiraud, M., Poquet, Y., Bonneville, M., and Fournie, J.J. (1999). 3-Formyl-1-butyl pyrophosphate A novel mycobacterial metabolite-activating human gammadelta T cells. J Biol Chem 274, 32079-32084.

Morita, C.T., Beckman, E.M., Bukowski, J.F., Tanaka, Y., Band, H., Bloom, B.R., Golan, D.E., and Brenner, M.B. (1995). Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells. Immunity 3, 495-507.

Compared with αβ TCRs, where a variety of structures have been determined since 1996, much less is known about γδ TCRs. [...] γδ T cells appear to respond to bacterial and parasitic infections (72) and primarily recognize phosphate-containing antigens (phosphoantigens) from mycobacteria by an unknown mechanism (72, 73).

72. Morita CT, Beckman EM, Bukowski JF, Tanaka Y, Band H, et al. 1995. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells. Immunity 3:495–507

73. Belmant C, Espinosa E, Poupot R, Peyrat MA, Guiraud M, et al. 1999. 3-Formyl-1-butyl pyrophosphate, a novel mycobacterial metabolite activating human γδ T cells. J. Biol. Chem. 274:32079–84

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1.1.1.3 The CD3 complex

The TcR is a complex consisting of the variable αβ chains noncovalently associated with the nonpolymorphic CD3 proteins. The CD3 proteins exist as a series of dimers including γε, δε, and ζζ associated with a single αβ heterodimer. These subunits lack enzymatic activity, but transduce signals via their immunoreceptor tyrosine-based activation motifs (ITAMs) (Reth, 1989). Tyrosine phosphorylation of the ITAMs serves as docking sites for interactions with other proteins. The earliest step in intracellular signaling following TcR ligation is the activation of src-family kinases p56lck and p59Fyn protein tyrosine kinases (PTKs), leading to phosphorylation of the CD3 ITAMs, followed by recruitment of Syk kinase family member ZAP-70 (ζ-associated phosphoprotein of 70 kDa) (Fig.3).

The phosphorylated CD3ζ is a recruitment site of the ZAP-70 PTK (Chan et al., 1992). The engagement of the TcR leads to Src family PTK activity resulting in ITAM phosphorylation and recruitment of ZAP-70. This converted the TcR: CD3 with no intrinsic enzymatic function into an active PTK associated molecular complex able to phosphorylate a spectrum of substrates leading to a myriad of downstream signals that, when integrated appropriately along with signals from other co-receptors, lead to T cell activation (Iwashima et al., 1994).

ZAP-70 targets are the transmembrane adapter protein linker for the activation of T cells (LAT) and the cytosolic adapter protein Src homology2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) (Bubeck Wardenburg et al., 1996; Zhang et al., 1998). These two adapters form the backbone of the complex that organizes effector molecules in a way that allows the activation of multiple signaling pathways. The loss of either LAT or SLP-76 results in a nearly complete loss of TcR signal transduction reminiscent of Syk/ZAP-70 or Lck/Fyn double-deficient T cells (Koretzky et al., 2006; Sommers et al., 2004; Zhang et al., 1999). LAT contains nine tyrosines that are phosphorylated upon TcR engagement, which bind the C-terminal SH2 domain of PLCγ1, the p85 subunit of phosphoinositide 3-kinase (PI3K), and the adapters growth factor receptor-bound protein 2 (GRB2) and GRB2-related adapter downstream of Shc (Gads) (Sommers et al., 2004). SLP-76 is then recruited to phosphorylated LAT via their mutual binding partner Gads (Liu et al., 1999).


Bubeck Wardenburg, J., Fu, C., Jackman, J.K., Flotow, H., Wilkinson, S.E., Williams, D.H., Johnson, R., Kong, G., Chan, A.C., and Findell, P.R. (1996). Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem 271, 19641-19644.

Iwashima, M., Irving, B.A., van Oers, N.S., Chan, A.C., and Weiss, A. (1994). Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136-1139.

Koretzky, G.A., Abtahian, F., and Silverman, M.A. (2006). SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6, 67-78.

Liu, S.K., Fang, N., Koretzky, G.A., and McGlade, C.J. (1999). The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr Biol 9, 67-75.

Reth, M. (1989). Antigen receptor tail clue. Nature 338, 383-384.

Sommers, C.L., Samelson, L.E., and Love, P.E. (2004). LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. Bioessays 26, 61-67.

Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., and Samelson, L.E. (1998). LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92.

Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., and Samelson, L.E. (1998). LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92.

[Page 3]

It was speculated, therefore, that tyrosine phosphorylation of the ITAMs might serve as docking sites for interactions with other proteins. Indeed, it was soon shown that phosphorylated CD3ζ (and later other ITAM-containing proteins) was a recruitment site of a 70 kDa phosphoprotein that turned out to be the syk kinase family member ZAP-70 (ζ-associated protein of 70 kDa) PTK (25). A model therefore emerged that engagement of the TCR led to src PTK activity resulting in ITAM phosphorylation and recruitment of ZAP-70. This converted the TCR with no intrinsic enzymatic function to an active PTK able to phosphorylate a spectrum of substrates leading to a myriad of downstream signals that, when integrated appropriately (along with signals from other co-receptors), leads to T cell activation (26).

[...]

Since identification of the TCR as a complex consisting of the variable αβ chains noncovalently associated with the non-polymorphic CD3 proteins, considerable work has gone

[Page 4]

It is now known that the CD3 proteins exist as a series of dimers including γε, δε, and ζζ associated with a single αβ heterodimer.

[Page 5]

The earliest step in intracellular signaling following TCR ligation is the activation of src (lck and fyn) PTKs leading to phosphorylation of the CD3 ITAMs. [...]

Among the most important of the ZAP-70 targets are the transmembrane adapter protein linker for the activation of T cells (LAT) and the cytosolic adapter protein src homology 2 (SH2)

[Page 6]

domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) (42,43). These two adapters form the backbone of the complex that organizes effector molecules in the correct spatiotemporal manner to allow for the activation of multiple signaling pathways. The importance of these adapters is underscored by studies showing that the loss of either LAT or SLP-76 results in a near complete loss of TCR signal transduction reminiscent of syk/ZAP-70 or lck/fyn doubly deficient T cells (44–46).

LAT contains nine tyrosines that are phosphorylated upon TCR engagement, which have been shown to bind the C-terminal SH2 domain of PLCγ1, the p85 subunit of phosphoinositide 3-kinase (PI3K), and the adapters growth factor receptor-bound protein 2 (GRB2) and GRB2- related adapter downstream of Shc (Gads) (reviewed in 45). SLP-76 is then recruited to phosphorylated LAT via their mutual binding partner Gads (47).



21. Reth M. Antigen receptor tail clue. Nature 1989;338:383–4. [PubMed: 2927501]

25. Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 1992;71:649–62. [PubMed: 1423621] Describes the cloning and initial characterization of ZAP-70, the syk family PTK essential for coupling the TCR to its downstream signaling machinery.

26. Iwashima M, Irving BA, van Oers NS, Chan AC, Weiss A. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 1994;263:1136–9. [PubMed: 7509083]

42. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 1998;92:83–92. [PubMed: 9489702]

43. Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem 1996;271:19641–4. [PubMed: 8702662]

44. Koretzky GA, Abtahian F, Silverman MA. SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 2006;6:67–78. [PubMed: 16493428]

45. Sommers CL, Samelson LE, Love PE. LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. Bioessays 2004;26:61–7. [PubMed: 14696041]

46. Zhang W, Sommers CL, Burshtyn DN, Stebbins CC, DeJarnette JB, Trible RP, Grinberg A, Tsay HC, Jacobs HM, Kessler CM, Long EO, Love PE, Samelson LE. Essential role of LAT in T cell development. Immunity 1999;10:323–32. [PubMed: 10204488]

47. Liu SK, Fang N, Koretzky GA, McGlade CJ. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr Biol 1999;9:67–75. [PubMed: 10021361] LAT−/− mice reveal a complete block in T cell development that, along with studies describing SLP-76−/− mice, exemplifies in vivo the essential role of adapter proteins for signal transduction.

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[13.] Analyse:Asa/Fragment 029 14 - Diskussion
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The continuous recirculation of naïve T cells and their subsequent migration to tissues following activation is crucial for maintaining protective immunity against invading pathogens. The preferential targeting of effector and memory T cells to tissues is instructed during priming and mediated by cell surface expressed adhesion receptors such as integrins.

Integrins are αβ heterodimeric cell surface adhesion molecules that mediate cell-extracellular matrix (ECM) and cell-cell interactions (Pribila et al., 2004), which are essential for T cell recirculation, migration into inflammatory sites and for a specific and effective immune response against foreign pathogens (Hynes, 2002; Shimizu et al., 1999).


Hynes, R.O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell 110, 673-687.

Pribila, J.T., Quale, A.C., Mueller, K.L., and Shimizu, Y. (2004). Integrins and T cell-mediated immunity. Annu Rev Immunol 22, 157-180.

Shimizu, Y., Rose, D.M., and Ginsberg, M.H. (1999). Integrins in the immune system. Adv Immunol 72, 325-380.

[Page 1 (Author Manuscript)]

The continuous recirculation of naïve T cells and their subsequent migration to tissue following activation is crucial for maintaining protective immunity against invading pathogens. The preferential targeting of effector and memory T cells to tissue is instructed during priming and mediated by cell surface expressed adhesion receptors such as integrins.

[Page 2 (Author Manuscript)]

Integrins are widely expressed cell surface adhesion molecules that mediate cell-extracellular matrix (ECM) and cell-cell interactions.2


2. Pribila JT, Quale AC, Mueller KL, Shimizu Y. Integrins and T cell-mediated immunity. Annu Rev Immunol 2004;22:157–80. [PubMed: 15032577]

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The interaction of αLβ2 with ICAM-1 is important for T cell entry into pLN and for T cell interactions with APCs. The α4β1 ligand VCAM-1 is expressed at low levels throughout the vasculature, but becomes upregulated on a wide array of tissue during inflammation (Henninger et al., 1997). MAdCAM-1, the major ligand for α4β7 is preferentially expressed at steady state in the mLN and Peyer’s patches, where it promotes entry of naïve T cells into these sites through a high affinity interaction (Berlin et al., 1993; Erle et al., 1994; von Andrian and Mackay, 2000). Both VCAM-1 and ICAM-1 are also expressed on the vasculature of the inflamed brain. In particular, VCAM-1 is known to promotes [sic] T cell entry through its interaction with α4β1 expressed on activated T cells (Engelhardt and Ransohoff, 2005).

Berlin, C., Berg, E.L., Briskin, M.J., Andrew, D.P., Kilshaw, P.J., Holzmann, B., Weissman, I.L., Hamann, A., and Butcher, E.C. (1993). Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185-195.

Engelhardt, B., and Ransohoff, R.M. (2005). The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26, 485-495.

Erle, D.J., Briskin, M.J., Butcher, E.C., Garcia-Pardo, A., Lazarovits, A.I., and Tidswell, M. 1994). Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol 153, 517-528.

Henninger, D.D., Panes, J., Eppihimer, M., Russell, J., Gerritsen, M., Anderson, D.C., and Granger, D.N. (1997). Cytokine-induced VCAM-1 and ICAM-1 expression in different organs of the mouse. J Immunol 158, 1825-1832.

von Andrian, U.H., and Mackay, C.R. (2000). T-cell function and migration. Two sides of the same coin. N Engl J Med 343, 1020-1034.

[Page 2 (Author Manuscript)]

The interaction of αLβ2 with ICAM-1 is important for T cell entry into pLN and T cell interactions with antigen-presenting cells (APCs). The α4β1 ligand VCAM-1 is expressed at low levels throughout the vasculature, but becomes upregulated on a wide array of tissue during inflammation.7 α4β7 is also reported to bind with low affinity to VCAM-1 in vitro and under some circumstances may play a role in pLN entry.8–10 MAdCAM-1, the major ligand for α4β7 is preferentially expressed at steady state in the mLN and PP, where it promotes entry of naïve T cells into these sites through a high affinity interaction.11–13

[Page 9 (Author Manuscript)]

Both VCAM-1 and ICAM-1 are expressed on the vasculature of the inflamed brain. In particular, VCAM-1 is known to promote T cell entry through its interaction with α4β1 expressed on activated T cells.125


7. Henninger DD, Panes J, Eppihimer M, Russell J, Gerritsen M, Anderson DC, Granger DN. Cytokine-induced VCAM-1 and ICAM-1 expression in different organs of the mouse. J Immunol 1997;158:1825–32. [PubMed: 9029122]

8. Ruegg C, Postigo AA, Sikorski EE, Butcher EC, Pytela R, Erle DJ. Role of integrin α4β7/α4βP in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol 1992;117:179–89. [PubMed: 1372909]

9. Day ES, Osborn L, Whitty A. Effect of divalent cations on the affinity and selectivity of α4 integrins towards the integrin ligands vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1: Ca2+ activation of integrin α4β1 confers a distinct ligand specificity. Cell Commun Adhes 2002;9:205–19. [PubMed: 12699089]

10. Berlin-Rufenach C, Otto F, Mathies M, Westermann J, Owen MJ, Hamann A, Hogg N. Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice. J Exp Med 1999;189:1467–78. [PubMed: 10224287]

11. Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression and function of the MAdCAM-1 receptor, integrin α4β7, on human leukocytes. J Immunol 1994;153:517–28. [PubMed: 7517418]

12. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A, Butcher EC. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993;74:185–95. [PubMed: 7687523]

13. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med 2000;343:1020–34. [PubMed: 11018170]

125. Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 2005;26:485–95. [PubMed: 16039904]

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Although typical protein antigens possess numerous immunogenic peptide sequences, only a few of these, the dominant epitopes, contribute to the development of the T-cell response against the whole protein. Epitopes that are immunogenic in peptide form, but do not participate in the immune response against the whole protein, are termed cryptic epitopes (Sercarz et al., 1993).

Cryptic epitopes have proven important in understanding self–non-self discrimination and autoimmunity (Lanzavecchia, 1995; Warnock and Goodacre, 1997). Several studies using transgene-derived neo-self antigens have shown, that immune tolerance extends only to dominant epitopes, and that T cells specific for cryptic epitopes may be immune competent (Cabaniols et al., 1994; Cibotti et al., 1992; Moudgil and Sercarz, 1993; Shih et al., 1997). Some autoimmune diseases are characterized by determinant spreading, in which the early stages of the disease are characterized by T cells reactive against one or a few dominant epitopes, while T-cell populations reactive against cryptic epitopes appear in the later stages of disease (Tuohy et al., 1998).


Cabaniols, J.P., Cibotti, R., Kourilsky, P., Kosmatopoulos, K., and Kanellopoulos, J.M. (1994). Dose-dependent T cell tolerance to an immunodominant self peptide. Eur J Immunol 24, 1743-1749.

Cibotti, R., Kanellopoulos, J.M., Cabaniols, J.P., Halle-Panenko, O., Kosmatopoulos, K., Sercarz, E., and Kourilsky, P. (1992). Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci U S A 89, 416-420.

Lanzavecchia, A. (1995). How can cryptic epitopes trigger autoimmunity? J Exp Med 181, 1945-1948.

Moudgil, K.D., and Sercarz, E.E. (1993). Dominant determinants in hen eggwhite lysozyme correspond to the cryptic determinants within its self-homologue, mouse lysozyme: implications in shaping of the T cell repertoire and autoimmunity. J Exp Med 178, 2131-2138.

Sercarz, E.E., Lehmann, P.V., Ametani, A., Benichou, G., Miller, A., and Moudgil, K. (1993). Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11, 729-766.

Shih, F.F., Cerasoli, D.M., and Caton, A.J. (1997). A major T cell determinant from the influenza virus hemagglutinin (HA) can be a cryptic self peptide in HA transgenic mice. Int Immunol 9, 249-261.

Tuohy, V.K., Yu, M., Yin, L., Kawczak, J.A., Johnson, J.M., Mathisen, P.M., Weinstock-Guttman, B., and Kinkel, R.P. (1998). The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol Rev 164, 93-100.

Warnock, M.G., and Goodacre, J.A. (1997). Cryptic T-cell epitopes and their role in the pathogenesis of autoimmune diseases. Br J Rheumatol 36, 1144-1150.

INTRODUCTION

[...] Although typical protein antigens possess numerous immunogenic peptide sequences, only a few of these, called dominant epitopes, contribute to the development of the T-cell response against the whole protein. Epitopes that are immunogenic in peptide form, but which do not participate in the immune response against the whole protein, are termed cryptic epitopes (reviewed in 1).

Cryptic epitopes have proven important in understanding self±non-self discrimination and autoimmunity.2,3 Several studies using transgene-derived neo-self antigens have shown that immune tolerance extends only to dominant epitopes, and that autologous T cells specific for cryptic epitopes of self proteins may be immune competent.4-7 Some autoimmune diseases are characterized by determinant spreading, in which the early stages are characterized by T cells reactive against one or a few dominant epitopes, while T-cell populations reactive against cryptic epitopes appear in the later stages of disease.8,9


1. SERCARZ E.E., LEHMANN P.V., AMETANI A., BENICHOU G.,MILLER A. & MOUDGIL K. (1993) Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11, 729.

2. WARNOCK M.G. & GOODACRE J.A. (1997) Cryptic T-cell epitopes and their role in the pathogenesis of autoimmune diseases. Br J Rheumatol 36, 1144.

3. LANZAVECCHIA A. (1995) How can cryptic epitopes trigger autoimmunity? J Exp Med 181, 1945.

4. SHIH F.F., CERASOLI D.M. & CATON A.J. (1997) A major T cell determinant from the influenza virus hemagglutinin (HA) can be a cryptic self peptide in HA transgenic mice. Int Immunol 9, 249.

5. CABANIOLS J.P., CIBOTTI R., KOURILSKY P., KOSMATOPOULOS K. & KANELLOPOULOS J.M. (1994) Dose-dependent T cell tolerance to an immunodominant self peptide. Eur J Immunol 24, 1743.

6. MOUDGIL K.D. & SERCARZ E.E. (1993) Dominant determinants in hen eggwhite lysozyme correspond to the cryptic determinants within its self-homologue, mouse lysozyme: implications in shaping of the T cell repertoire and autoimmunity. J Exp Med 178, 2131.

7. CIBOTTI R., KANELLOPOULOS J.M., CABANIOLS J.P. et al. (1992) Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci USA 89, 416.

8. TUOHY V.K., YU M., YIN L. et al. (1998) The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol Rev 164, 93.

9. SERCARZ E.E. (1998) Immune focusing vs diversification and their connection to immune regulation. Immunol Rev 164, 5.

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[1.] Analyse:Asa/Fragment 029 25 - Diskussion
Bearbeitet: 9. October 2014, 00:07 Graf Isolan
Erstellt: 8. October 2014, 20:27 (Graf Isolan)
Asa, DeNucci et al 2009, Fragment, SMWFragment, Schutzlevel, Unfertig, Verschleierung

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Untersuchte Arbeit:
Seite: 29, Zeilen: 25-29
Quelle: DeNucci et al 2009
Seite(n): 2, Zeilen: 19-24
Naïve T cells express a homogeneous array of cell surface molecules that promotes recirculation through the secondary lymphoid organs of the body, including the spleen, peripheral lymph nodes (pLN), mesenteric lymph nodes (mLN) and Peyer’s patches (PP) of the small intestine. Naïve T cells express low levels of the αLβ2 (LFA-1), α4β1 (VLA-4) and α4β7 (LPAM) integrins, which bind ICAM-1, VCAM-1, and MAdCAM-1, [respectively (Springer, 1995).]

Springer, T.A. (1995). Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 57, 827-872.

Naïve T cells express a fairly homogeneous array of cell surface molecules that promotes recirculation through the SLOs of the body, including the spleen, peripheral lymph nodes (pLN), mesenteric lymph node (mLN) and peyer’s patches (PP) of the small intestine. Naïve T cells express low levels of the αLβ2 (LFA-1), α4β1 (VLA-4) and α4β7 (LPAM) integrins, which bind ICAM-1, VCAM-1, and MAdCAM-1, respectively (Fig. 1).6

6. Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 1995;57:827–72. [PubMed: 7778885]

Anmerkungen

Though identical with identical reference nothing has been marked as a citation.

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Quellen

Quelle Autor Titel Verlag Jahr Lit.-V. FN
Asa/DeNucci et al 2009 Christopher C. DeNucci, Jason S. Mitchell, and Yoji Shimizu Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there 2009 no no
Asa/Janeway 2002 Charles A. Janeway, Jr. and Ruslan Medzhitov Innate immune recognition 2002 no no
Asa/Rudolph et al 2006 Markus G. Rudolph, Robyn L. Stanfield, and Ian A.Wilson How TCRs Bind MHCs, Peptides, and Coreceptors 2006 ja ja
Asa/Smith-Garvin et al 2009 Jennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan T Cell Activation 2009 no yes
Asa/Thatcher et al 2000 T. H.Thatcher, D. P. O'Brien, S. Altuwaijri, R. K. Barth Increasing the frequency of T-cell precursors speci®c for a cryptic epitope of hen-egg lysozyme converts it to an immunodominant epitope 2000 no no


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