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Crosstalk between autoreactive T cells and alveolar type II epithelial cells in inflammation and tolerance

von Dr. Marcus Gereke

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[1.] Mag/Fragment 028 01 - Diskussion
Zuletzt bearbeitet: 2014-03-10 18:09:09 Graf Isolan
Fragment, Gesichtet, Mag, OGarra and Vieira 2004, SMWFragment, Schutzlevel sysop, Verschleierung

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4.1 Naturally occurring CD4+CD25+ regulatory T cells

The CD4+CD25+ regulatory T cells are currently the focus of intensive research and were first described in the early 1970s by Gershon and colleagues (Gershon et al., 1974). These cells represent 5-10% of the CD4+ T lymphocytes in healthy adult mice and humans and are thought to perform a specialized role in controlling both the innate and the adaptive immune system. Although easily identified and isolated from unmanipulated mice and humans on the basis of CD25 expression, this chain of the IL-2(R) receptor is also expressed on activated T cells (Maloy et al., 2003; Sakaguchi et al., 2001; Shevach, 2002). So far, no characteristic stable surface marker has been assigned to Treg cells. Additional markers expressed by these cells include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Read et al., 2000; Takahashi et al., 2000) and glucocorticoid induced tumor necrosis factor receptor (TNFSR18) (McHugh et al., 2002; Shimizu et al., 2002), which were initially implicated in the mechanism of Treg action. However, both of these molecules are also expressed by nonregulatory T cells after activation. Various groups identified the forkhead/winged helix transcription factor Foxp3 as a marker for both CD25+ Treg cells and CD25- cell that have regulatory activity (Fontenot et al., 2003; Hori et al., 2003).


Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003 Apr; 4 (4): 330-6. Epub 2003 Mar 3.

Gershon RK, Lance EM, Kondo K Immuno-regulatory role of spleen localizing thymocytes. J Immunol. 1974 Feb; 112 (2): 546-54.

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003 Feb 14; 299 (5609): 1057-61. Epub 2003 Jan 9.

Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003 Jan 6; 197 (1): 111-9.

McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002 Feb; 16 (2): 311-23.

Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000 Jul 17; 192 (2): 295-302.

Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001 Aug; 182: 18-32. Review.

Sakaguchi S, Takahashi T, Yamazaki S, Kuniyasu Y, Itoh M, Sakaguchi N, Shimizu J. Immunologic self tolerance maintained by T-cell-mediated control of self-reactive T cells: implications for autoimmunity and tumor immunity. Microbes Infect. 2001 Sep; 3 (11): 911-8. Review.

Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002 Jun; 2 (6): 389-400. Review.

Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002 Feb; 3 (2): 135-42. Epub 2002 Jan 22.

Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000 Jul 17; 192 (2): 303-10.

[page 801]

Naturally occurring CD4+CD25+ Treg cells

The CD4+CD25+ T cell subset is currently the focus of intensive research. These cells represent 5-10% of the CD4+ T lymphocytes in healthy adult mice and humans and are thought to perform a specialized role in controlling both the innate and the adaptive immune system2,3,17. Although easily identified and isolated from unmanipulated mice and humans on the basis of CD25 expression, this chain of the IL-2R is also expressed on activated T cells2,3,17. Thus far, no characteristic stable surface marker has been ascribed to Treg cells. Additional markers expressed by these cells include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)18,19 and glucocorticoid-induced tumor necrosis factor receptor20,21, which were initially

[page 802]

implicated in the mechanism of Tregaction. However, both of these molecules are also expressed by nonregulatory T cells, after activation. [...]

The forkhead/winged helix transcription factor Foxp3 was shown to be specifically expressed by CD25+ Treg cells, as well as by CD25- T cells with regulatory activity23–25.


2. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

3. Shevach, E.M. CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

17. Maloy, K.J. et al. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

18. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

19. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

20. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).

21. McHugh, R.S. et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

23. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

24. Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

25. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

Anmerkungen

The source is not mentioned here, although the entire passage including references to the literature is taken from it (apart from a minor historical note at the beginning).

Note: there are two entries "Sakaguchi et al. 2001" in the bibliography of the thesis.

Sichter
(Hindemith) Schumann

[2.] Mag/Fragment 028 23 - Diskussion
Zuletzt bearbeitet: 2014-03-15 12:41:29 Graf Isolan
Bluestone Abbas 2003, Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop, Verschleierung

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The resident regulatory cells that develop in the thymus are generated in a burst of activity during the early stages of fetal and neonatal T cell development (Sakaguchi et al., 2001). They are polyclonal on the basis of diverse TCR usage (Shevach, 2002), and they are potentially capable of recognizing diverse self-antigens.

The promiscuous gene expression of many self tissue-specific proteins in the medullar epithelial cells of the thymus is described as a potential mechanism to ensure central tolerance to peripheral self-antigens, because this self-antigen expression in the thymus might lead, among other things, to the deletion of immature autoreactive T cells (Derbinski et al., 2001). However, it is possible that these self proteins are expressed at low levels and, additionally, by only some of the epithelial [cells, making clonal deletion a rather ineffective means of inducing tolerance to peripheral antigens.]

[page 253]

The resident regulatory cells that develop in the thymus are generated in a burst of activity during the early stages of fetal and neonatal T-cell

[page 254]

development7. They are polyclonal on the basis of diverse TCR usage3, and they are potentially capable of recognizing diverse self-antigens. Kyewski and colleagues8, have shown that messenger RNA transcripts encoding many tissue-specific proteins are expressed by ‘islands’of medullary epithelial cells in the thymus. It has been proposed that this promiscuous gene expression might be a mechanism to ensure central tolerance to peripheral self-antigens. Self-antigens that are expressed by these medullary epithelial cells in the thymus might delete immature self-reactive T cells. However, it is probable that these self-proteins are expressed at low levels and by only some of the epithelial cells, making clonal deletion a rather ineffective means of inducing tolerance to peripheral antigens.


7. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

3. Shevach, E. M. CD4+CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002)

8. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).

Anmerkungen

The source is not indicated. Continued on the next page.

Sichter
Schumann


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