{Reference Type}: Journal Article
{Title}: LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.
{Author}: Ngiow SF;Manne S;Huang YJ;Azar T;Chen Z;Mathew D;Chen Q;Khan O;Wu JE;Alcalde V;Flowers AJ;McClain S;Baxter AE;Kurachi M;Shi J;Huang AC;Giles JR;Sharpe AH;Vignali DAA;Wherry EJ;
{Journal}: Cell
{Volume}: 187
{Issue}: 16
{Year}: 2024 Aug 8
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2024.07.018
{Abstract}: 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.