CD5 regulates the heterogenous depot of NF kappa B available for T cell activation

Abstract T cells bearing receptors to the same antigen often differ considerably in their ability to respond. We hypothesized that variations in intracellular signaling molecules in T cells may underlie these cell-to-cell heterogeneities. We found that the expression levels of PLCγ and IκBα, varied considerably between individual peripheral T cells. The ~1000-fold variation in IκBα levels, but that not of PLCγ, strictly correlated with surface levels of CD5. CD5 is typically used as a marker for T cell self-reactivity and differences in responses between CD5-high and -low cells is attributed to the self-awareness of the TCR. Our data suggested that CD5 directly regulates the NFκB pathway to modulate T cell responses. Accordingly, ablating CD5 using germline or conditional knock-out mice resulted in a significant reduction in IκBα. This regulation was independent of SHP-1 and casein kinase II and not evident in mRNA levels, suggesting a previously unknown post-translational mechanism. Overexpression of CD5 in TCR-deficient cells also increased basal IκBα levels indicating independence from TCR signaling. Intriguingly, cells with higher CD5 and IκBα expression maintained a proportionally greater amount of NFκBp65 in a cellular reservoir. This suggests that CD5-high T cells with a greater NFκB reservoir might allow for a more robust NFκB-dependent gene expression. Consistent with this postulate, we found that CD5-high thymocytes survived ex vivo better than CD5-low ones, but only when NFκB signaling was intact. These data suggest a key role for CD5 in the control of T cell heterogeneity, independent of the self-reactivity of a TCR itself.