Lag3 and PD-1 pathways preferentially regulate NFAT-dependent TCR signalling programmes during early CD4⁺ T cell activation.

ABSTRACT:

Introduction

Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early stages of CD4⁺ T cell activation remains unclear.

Methods

Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4⁺ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOS^hi T follicular helper cell differentiation.

Results

NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4

SUBMITTER: Sheriff L 

PROVIDER: S-EPMC12066006 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature