Reygn Done

Abstract Anti-Lag3 and anti-PD-1 combination immunotherapy for melanoma has received recent regulatory approval, yet its mechanism of action is unclear, particularly for CD4+ T cells. Here, we determined the roles of the Lag3 and PD-1/PD-L1 pathways during CD4+ T cell activation in vivo. During primary immune responses, Lag3 played a redundant role with the PD1/PD-L1 axis dominant in regulating early CD4+ T cell activation.

Abstract Strong tolerogenic signalling recalibrates CD4+ T cell activation in part via the PD-1 pathway. However, the contribution of other checkpoints is unknown. Here, we reveal that Lag3 and PD-L1 pathways are the major regulators of TCR signalling in adaptively tolerised CD4+ T cells. Lag3 and PD-L1 co-blockade (CB) drove additive and synergistic changes in T cell activation, resulting in a transcriptional profile dominated by a NFAT-biased/ T follicular helper cell signature.