CD5 dynamically calibrates basal NF-KB signaling in T cells during thymic development and peripheral activation

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are upregulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We find that CD5 alters the basal activity of the NF-kB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NFκB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NFκB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This post-translationally stabilized cellular NFkB depot potentially confers a survival advantage to CD5hi T cells over CD5lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide induced TCR signals lead to the upregulation of CD5, which subsequently maintains a proportional reserve of NFκB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation. 4 cell types (CD4+CD5lo, CD4+CD5hi, CD8+CD5lo, CD8+CD5hi) x 4 biological replicates = 16 samples x 2 technical replicates