Role of the MHC-Bound Self-Peptide Repertoire in CD4 T Cell Development and Differentiation

Another focus of research in our lab has been the role of self-peptide:MHC class II complexes in shaping CD4 T cell receptor (TCR) repertoire in the thymus and in the maintenance and homeostatic control of CD4 T cells in the periphery. We have developed a novel experimental system for studying the contribution of peptides to positive selection of CD4 T cells. This system relies on the overexpression of a known transgene-encoded peptide by the majority of MHC class II molecules in vivo and allows for manipulation of the diversity of peptides displayed by MHC class II molecules. Studies of the peptide requirements for positive selection in this system indicate that the interaction of self-peptides and TCRs during positive selection is specific and that low-abundance peptides are major contributors to the positive selection of CD4 T cells. Nevertheless, utilization of several transgenic mice allowed us to detect a subset of CD4 T cells selected by a given peptide by comparing mice overexpressing one peptide with mice overexpressing two MHC class II–bound peptides.

Surprisingly, the self-MHC reactivity of CD4 T cells varied greatly, depending on which peptide was overexpressed. These differences in self-MHC reactivity were mediated through positive selection, not negative selection, demonstrating that interactions with individual peptide-MHC complexes during positive selection are sufficiently unique that the specificities of T cells selected are distinct. These results suggest that certain peptide-MHC complexes select TCR specificities with greater self-MHC reactivity than others. (A grant from the National Institutes of Health provided support for these studies.)

Recently, by studying TCR transgenic thymocytes selected in the presence of a skewed repertoire of MHC class II–bound peptides, we found that a signal even weaker than that driving positive selection can be perceived through the TCR of immature thymocytes. These signals are not sufficient for promoting positive selection but are able to up-regulate CD69 and CD5, a known negative regulator of TCR signal transduction. Thus the induction stage of thymocyte development may occur on peptide ligands distinct from those that promote complete maturation. These results support a model in which immature DP thymocytes may be able to interact with a wide range of thymic peptide-MHC complexes in a weakly cross-reactive manner during their migration through the thymus. The up-regulation of CD5 that subsequently occurs may tune TCR sensitivity by raising the threshold of activation, which narrows the spectrum of ligands that can select thymocytes and may be important for maintaining tolerance to the self-peptide.