A role for MHC-mediated signalling in the functional and phenotypic heterogeneity of naive T cells (IRC8P.454)

Variability in cellular activation in the immune system can have diverse consequences, resulting in heterogeneity in effector programming and function as well as in cell survival. While examining relationships between lymphocyte heterogeneity and functionality, we find that apparently unimodally distributed coreceptor heterogeneity among naive T cells, simplistically expected to be due to intrinsic noise, is not only correlated with major functional variation but is modulated by extrinsic microenvironmental cues in vivo. Thus, when naive T cells from young mice are separated into coreceptor-hi and coreceptor-lo subsets, we find that coreceptor-lo cells are smaller, have higher CD5 levels, respond poorly, are more susceptible to death, and show altered effector differentiation. Human coreceptor-lo and coreceptor-hi naive T cells show similar differences. Coreceptor-lo and coreceptor-hi subsets of 9single-positive9 (SP) thymocytes do not show these differences, whereas peripheral coreceptor-lo and coreceptor-hi subsets of naive T cells from TCR-transgenic mice do. Adoptive transfer-mediated parking in vivo in MHC-sufficient but not in MHC-deficient mice causes reduction in coreceptor levels, increase in CD5 levels and hyporesponsiveness in naive T cells. Naive T cells from aged mice show similar phenotypic and functional differences. Thus, our data show complex roles for tonic signaling in the functional heterogeneity of naive T cell populations.