Self-Recognition and the Regulation of Cd4+ T Cell Survival
CD4+ T cells differentiate in the thymus from committed precursors to mature naive cells ready for peripheral circulation. Successful maturation depends on adequate but not excessive signaling upon T cell receptor (TCR) engagement of selfpeptide/MHC class II molecule ligands present in the thymic environment. Persistent TCR signaling throughout development from the CD4+CD8+ to the CD4+ state is required for completion of the developmental process. Recent work has suggested that a continuation of this signaling is essential for sustained survival of CD4+ T cells once they leave the thymus but our studies suggest otherwise. Although we found clear evidence for active TCR signaling involving recognition of self-ligands in peripheral lymphoid tissues, we did not see a substantial effect of loss of such signaling on the life-time of naive CD4+ T cells. Based on a careful review of the literature, we conclude that essentially all previous claims that MHC class II recognition plays a significant role in the survival of CD4+ T cells can be reinterpreted as an effect of self-recognition on proliferation in lymphopenic environments, maintaining population numbers without a marked effect on individual cell viability. We propose a possible explanation for why, in contrast, the viability of naive CD8+ T cells appears to show such self-MHC dependence and suggest that a primary function of self-recognition by T cells may be to enhance responses to foreign antigen.
KeywordsTyrosine Recombination Microbe Tetracycline Doyle
Unable to display preview. Download preview PDF.
- 10.J. Kirberg, A. Berns and H. von Boehmer, Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded moleculesJ Exp Med186, 12691275 (1997).Google Scholar
- 11.D. Nesic and S. Vukmanovic, MHC class I is required for peripheral accumulation of CD8+ thymic emigrantsJlmmunol160, 3705–3712 (1998).Google Scholar
- 12.M. A. Markiewicz, C. Girao, J. T. Opferman, J. Sun, Q. Hu, A. A. Agulnik, C. E. Bishop, C. B. Thompson and P. G. Ashton-Rickardt, Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex moleculesProc Natl Acad Sci USA95, 30653070 (1998).Google Scholar
- 25.J. R. Dorfman, I. I. Stefanova, K. Yasutomo and R. N. Germain, xResponse to ‘Class Il essential for CD4 survival’, 2, 136–137 (2001).Google Scholar
- 29.E. F. Petricoin, 3rd, S. Ito, B. L. Williams, S. Audet, L. F. Stancato, A. Gamero, K. Clouse, P. Grimley, A. Weiss, J. Beeler, D. S. Finbloom, E. W. Shores, R. Abraham and A. C. Lamer, Antiproliferative action of interferon-a requires components of T- cell-receptor signallingNature390, 629–632 (1997).CrossRefPubMedGoogle Scholar
- J. R. Dorfman and R. N. Germain, Mhc-dependent survival of naïve T cells? A complicated answer to a simple questionMicrobes and Infectionin press, (2002).Google Scholar