LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor...

Exhausted CD8 T (T_ex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). T_ex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on T_ex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating T_ex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and T_ex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2⁺ subset of T_ex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating T_ex cells.