%0 Journal Article
%T LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.
%A Ngiow SF
%A Manne S
%A Huang YJ
%A Azar T
%A Chen Z
%A Mathew D
%A Chen Q
%A Khan O
%A Wu JE
%A Alcalde V
%A Flowers AJ
%A McClain S
%A Baxter AE
%A Kurachi M
%A Shi J
%A Huang AC
%A Giles JR
%A Sharpe AH
%A Vignali DAA
%A Wherry EJ
%J Cell
%V 187
%N 16
%D 2024 Aug 8
%M 39121847
%F 66.85
%R 10.1016/j.cell.2024.07.018
%X Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex 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 Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex 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 Tex cells.