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Untersuchte Arbeit:
Seite: 31, Zeilen: 1ff (entire page)
Quelle: Bluestone_Abbas_2003
Seite(n): 254, 255, Zeilen: 254: col. 3: 39-45, 49-60 - 255: col 1: 1-11, 16-19, 26-52
Moreover, in contrast to natural Treg cell, which are fully functional at the time of thymic export as a consequence of strong TCR engagement, the development of adaptive Treg cells in the periphery might be triggered by low-affinity antigen or altered TCR signal transduction. These antigen-stimulated adaptive Treg cells are not functional without activation by further exposure to antigens – such as during infection, organ transplantation under cover of certain immunomodulatory therapies, or ectopic expression of non-self-antigens (Apostolou et al., 2002; Belkaid et al., 2002; Fuss et al., 2002; Kingsley et al., 2002; Powrie, 2003). Concerning the antigen specificity of adaptive Treg cells, it is interesting to speculate that these cells have a diverse repertoire, which might be expanded as a consequence of fortuitous cross-reactivities with foreign proteins. It is possible that the TCR repertoire of adaptive Treg cells is self-antigen specific, but that these cells are triggered in an inflammatory environment to promote bystander suppression through the production of suppressive cytokines.

It is important to note that unlike natural Treg cells, adaptive Treg cells might not require costimulation through CD28 for their development or function (Taylor et al., 2002). Interestingly, IL-2 might promote the development and function of both types of Treg cells, on the basis of studies showing the total absence of Treg cells in IL-2 receptor-deficient mice (Malek et al., 2002; Furtado et al., 2002).

4.3 Mechanism of suppression

In addition to potential differences in terms of TCR repertoire and differentiation state, it is proposed that natural and adaptive subsets of Treg cells differ in their mechanism of action. Adaptive Treg cells mediate their inhibitory activities by producing immunosuppressive cytokines, such as TGF-ß and IL-10 (Kingsley et al., 2002; Nakamura et al., 2001). In contrast, natural Treg cells, at least in vitro, function by a cytokine-independent mechanism, which presumably involves direct interactions with responding T cells or antigen-presenting cells (Shevach, 2002). This contact-dependent mechanism of suppression has been shown most convincingly by CD4+CD25+ natural Treg cells employed in in vitro models of suppression, whereas cytokine-mediated suppression has been best established for peripheral adaptive Treg [cells in vivo.]

[page 254]

Moreover, in contrast to natural TReg cells, which are fully functional at the time of thymic export as a consequence of strong TCR engagement, the development of adaptive TReg cells in the periphery might be triggered by low-affinity antigen or altered TCR signal transduction. [...] These antigen-stimulated adaptive TReg cells are not functional without activation by further exposure to antigens — such as during infection, organ transplantation under the cover of certain immunomodulatory therapies, or ectopic expression of non-self antigens19,26–29. What remains unclear is the antigen specificity of the adaptive TReg cells. Given that they often seem to develop in the context of infection or organ transplantation, it is interesting to speculate that adaptive TReg cells have a diverse repertoire, which is perhaps

[page 255]

expanded as a consequence of fortuitous cross-reactivities with foreign proteins. However, as foreign-antigen-specific TReg cells have been described only rarely, it remains possible that the TCR repertoire of adaptive TReg-cell populations (in particular, the CD4+CD25+ subset) is self-antigen specific, but that these cells are triggered in an inflammatory environment to promote bystander suppression through the production of suppressive cytokines (see below). [...] However, it is important to note that unlike natural TReg cells, adaptive TReg cells might not require co-stimulation through CD28 for their development or function. [...] Interestingly, IL-2 might promote the development and function of both types of TReg cell, on the basis of studies showing the total absence of TReg cells in IL-2R-deficient mice11,31.

Mechanisms of suppression

In addition to potential differences in terms of TCR repertoire and differentiation state, we propose that the natural and adaptive subsets of TReg cells differ in their mechanism of action. Many studies have indicated that what we term adaptive TReg cells mediate their inhibitory activities by producing immunosuppressive cytokines, such as transforming growth factor-β (TGF-β) and IL-10 (REFS 19,32; L. Chatenoud, personal communication). By contrast, natural TReg cells, at least in vitro, function by a cytokine-independent mechanism, which presumably involves direct interactions with responding T cells or antigenpresenting cells3. This contact-dependent mechanism of suppression has been shown most convincingly by CD4+CD25+ natural TReg cells tested in in vitro models of suppression, whereas cytokine-mediated suppression has been best established for peripheral adaptive TReg cells in vivo33.


19. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

26. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002).

27. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

28. Fuss, I. J., Boirivant, M., Lacy, B. & Strober, W. The interrelated roles of TGF-β and IL-10 in the regulation of experimental colitis. J. Immunol. 168, 900–908 (2002).

29. Powrie, F. in Novartis Foundation Symposium 252. Generation and Effector Functions of Regulatory Lymphocytes (Wiley, Europe) (in the press).

11. Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ- deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

31. Furtado, G. C., de Lafaille, M. A., Kutchukhidze, N. & Lafaille, J. J. Interleukin-2 signaling is required for CD4+ regulatory T-cell function. J. Exp. Med. 196, 851–857 (2002).

19. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

32. Nakamura, K., Kitani, A. & Strober, W. Cell contactdependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor-β. J. Exp. Med. 194, 629–644 (2001).

33. Bach, J. F. & Chatenoud, L. Tolerance to islet autoantigens and type I diabetes. Annu. Rev. Immunol. 19, 131–161 (2001).

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