Inhibitory signaling axes in CLL. Up-regulation of CD200, CD270, CD274, and CD276 induces impaired actin polymerization and immunological synapse formation in CLL T cells. This results in nonpolarized degranulation and impaired cytotoxicity. CD200 also promotes the differentiation of CD4⁺ T cells into Tregs, which express CD152(CTLA-4). CD270(HVEM) and CD274(PD-L1) interact with their ligands, CD160 and CD279(PD-1), respectively, to inhibit T-cell activation and proliferation. Chronic antigenic stimulation of T cells by either TAAs expressed by the CLL cells or other auto-antigens/exogenous antigens drives T-cell exhaustion and increased expression of inhibitory ligands such as CD279(PD-1), CD160, and CD244.