What’s self got to do with it: Sources of heterogeneity among naive T cells

There is a long-standing assumption that naive CD4+ and CD8+ T cells are largely homogeneous populations despite the extraordinary diversity of their T cell receptors (TCR). The self-immunopeptidome plays a key role in the selection of the naive T cell repertoire in the thymus, and self-peptides are also an important driver of differences between individual naive T cells with regard to their subsequent functional contributions to an immune response. Accumulating evidence suggests that as early as the β-selection stage of T cell development, when only one of the recombined chains of the mature TCR is expressed, signaling thresholds may be established for positive selection of immature thymocytes. Stochastic encounters subsequently made with self-ligands during positive selection in the thymus imprint functional biases that a T cell will carry with it throughout its lifetime, although ongoing interactions with self in the periphery ensure a level of plasticity in the gene expression wiring of naive T cells. Identifying the sources of heterogeneity in the naive T cell population and which functional attributes of T cells can be modulated through post-thymic interventions versus those that are fixed during T cell development, could enable us to better select or generate T cells with particular traits to improve the efficacy of T cell therapies.