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

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 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.