LAG-3 marks effector to regulatory evolution of Th1 immunity in influenza

Abstract

Abstract Naïve CD4+ T cells respond in influenza with T-bet expression, a transcription factor up-regulated with Th1 commitment. We report concomitant LAG-3 expression on these Th1 committed cells with evolution into regulatory T cells. LAG-3 expression increases with activation as revealed by CFSE cell division study. Cells with moderate LAG-3 expression produce IFN-γ and contribute to inflammation and disease. They no longer produce IFN-γ with higher LAG-3 expression upon further activation. High LAG-3 cells suppress and decouple effector function from the preserved proliferation of CD8+ T cells. They restrain inflammation with facilitated viral clearance and ameliorate the disease of severe influenza. Foxp-3+CD4+ T cells suppress both effector and proliferative responses with impaired viral clearance and they are less potent in disease amelioration. Principal component analysis of genome-wide expression further confirmed the stepwise evolution from effector to regulatory T cells. Regulatory genes are up-regulated progressively from LAG-3Neg to LAG-3Med and to LAG-3High cells.