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 self-peptide/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.