Activation and lineage specific Lag3 expression dynamics in T cells.

Co-inhibitory receptors are essential checkpoints to restrain excessive T cell activation. While PD1 and CTLA4 have been extensively studied, the biology of lymphocyte activation gene 3 (Lag3), an emerging target for checkpoint blockade immunotherapy, remains less understood. In this study, we show that Lag3, though largely intracellular in resting T cells, exhibits unexpected dynamic cycling even without stimulation. The Lag3 cycling are influenced by lineage and differentiation status, particularly within memory and regulatory T cell subsets. Moreover, Lag3-like cycling patterns were also observed in other co-receptors with stimulatory and inhibitory properties. Mechanistically, endosomal trafficking is important for Lag3 cycling, whereas the cytoplasmic domain of Lag3 appears to be largely dispensable for this process. T cells engaging in Lag3 cycling exhibit a survival and proliferation advantage in both lymphpenic and lymphoreplete conditions. Together, these findings establish Lag3 cycling as a regulated and functionally important process, providing new insights into the biology of Lag3 in T cells.