CD5 dynamically calibrates basal NF-xB 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 up-regulated 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 (CD5(hi)) 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 found that CD5 alters the basal activity of the NF-kappa B signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-kappa B inhibitor I kappa B alpha. Consistent with this, resting CD5(hi) T cells expressed more of the NF-kappa B p65 protein than CD5(lo) cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-kappa B depot potentially confers a survival advantage to CD5hi T cells over CD5(lo) ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-kappa B in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.