Glucocorticoid regulation of the mTORC1 pathway modulates CD4(+) T cell responses during infection

OBJECTIVES: Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4(+) T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4(+) T cells during infection. METHODS: We consistently measured FOXP3, inflammatory cytokines and phospho‐S6 ribosomal protein levels in CD4(+) T cells from patients undergoing conventional GC treatment. Using Foxp3(EGFP) animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4(+) T cells under the influence of GCs. RESULTS: GCs dynamically altered the expression pattern of FOXP3 in CD4(+) T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4(+) T cells. Dynamic activation of the mTORC1 signaling modified the GC‐dampened immunoregulatory capacity of CD4(+) T cells by phenotypically and functionally bolstering the FOXP3(+) Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC‐dampened immunoregulatory capacity of CD4(+) T cells. CONCLUSION: These findings highlight a novel mTORC1‐mediated mechanism underlying CD4(+) T cell immunity in the context of conventional GC treatment.