CD5-dependent CK2 activation pathway regulates T cell activation and threshold for anergy (143.27)

Abstract

Abstract We have reported that a major biological activity of CD5 is to regulate the survival of activated T cells, a property mediated by the CD5-dependent CK2 activation pathway. In order to address the physiological role of the CD5-dependent CK2 activation pathway in T cell activation, the generation of Th effector cells, and autoimmunity, we generated by gene targeting a mouse (CD5ΔCK2BD) that expressed CD5 lacking the ability to bind and activate CK2. CD4 and CD8 T cells from CD5ΔCK2BD mice exhibited enhanced AICD and hyporeactivity to antigen receptor stimulation compared to T cells from CD5WT and CD5-/- mice. The ability to mobilize calcium and upregulate CD69 were greatly enhanced in CD5-/- T cells but not in CD5WT T cells or CD5ΔCK2BD T cells, indicating that the CD5-dependent CK2 activation pathway did not regulate TCR-proximal signaling pathways. CD5-/- mice developed attenuated experimental autoimmune encephalomyelitis (EAE) when immunized with 150 μg MOG, yet the disease in CD5ΔCK2BD mice was comparable to that seen in CD5WT mice. In contrast, immunization with tolerogenic doses of MOG resulted in attenuated EAE in CD5WT mice but not in CD5-/- and CD5ΔCK2BD mice. The results indicated that loss of the CD5-dependent CK2 pathway made T cells refractory to induction of anergy, a prediction that was recapitulated in in vitro recall assays. Our results reveal a novel role for CD5 in setting thresholds for anergy in T cells. Supported by grants from the NIH and NMSS.