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

Abstract

Abstract 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 Foxp3EGFP 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.

Keywords

• FOXP3
• glucocorticoid
• immunomodulation
• inflammation
• mTOR complex 1
• T cell