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

ABSTRACT: 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-?B signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-?B inhibitor I?B?. Consistent with this, resting CD5^hi T cells expressed more of the NF-?B p65 protein than CD5^lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-?B depot potentially confers a survival advantage to CD5^hi 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-?B in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.

SUBMITTER: Matson CA 

PROVIDER: S-EPMC7322041 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature