UC Berkeley

During positive selection, thymocytes avoid death by sensing and adjusting to homeostatic signals from self-peptide:major histocompatibility complexes (MHCs) in a process known as functional tuning. As a result, thymocytes mature into a diverse repertoire of T cells with different degrees of self reactivity, and cells with high and low self reactivity exhibit differences in effector function in the periphery. CD5 is a known tuning molecule for thymocytes with high self reactivity. However, the molecules involved in the functional tuning of cells with low self reactivity during positive selection are yet to be identified, and overall little is known about the positive selection of T cells with low self reactivity. To investigate this, we identified TG6, a functionally relevant, MHCI-restricted TCR transgenic (tg), as a novel model for studying CD8 T cells with low self reactivity. Using this model, we show that cells with low self reactivity have relatively brief TCR signals, not associated with a migratory pause, during positive selection, and that these truncated signals are correlated with delayed progress through positive selection. Cells with low self reactivity can take a week or more to mature—compared to just 3 days for cells with high self reactivity. Though all polyclonal thymocytes have increased TCR sensitivity at the beginning of positive selection, we provide evidence that cells with low self reactivity retain a gene expression signature consistent with increased TCR sensitivity late into development. Furthermore, we identify two genes, Kcna2 and Tmie, that have high expression in cells with low self reactivity and may increase TCR sensitivity. The expression of Kcna2 and Tmie is set in cells with low self reactivity during positive selection and maintained in the periphery—a characteristic expression pattern of functional tuning genes. Our results fit with a model where self reactivity directs the rate of TCR signal accumulation, TCR sensitivity, and the time to reach maturation. These differences in positive selection may be important for appropriate functional tuning of T cells, based on their self reactivity.