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

Significance CD5 is a surface receptor that negatively regulates T cell activation, but T cells expressing more CD5 have been shown to survive better in the effector/memory phase after pathogenic insult. Our data suggest a mechanistic framework for this duality, by identifying the NF-κB pathway as a target of CD5 signaling. CD5 controls the amounts of lymphocyte IκBα independently of the canonical binding partner SHP-1 and in addition to T cell receptor signals. The increased basal levels of NF-κB transcription factors in CD5hi cells also conferred an NF-κB–dependent survival advantage. 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 (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 found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NF-κB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB 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 signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.