Reciprocal Regulation of Glycolysis-Driven Th17 Pathogenicity and Regulatory T Cell Stability by Cdc42

Abstract

A balance between Th17 cells and regulatory T cells (Tregs) is important for host immunity and immune tolerance. The underlying molecular mechanisms remain poorly understood. Here we have identified Cdc42 as a central regulator of Th17/Treg balance. Deletion of Cdc42 in T cells enhanced Th17 differentiation but diminished induced Treg differentiation and suppressive function. Treg-specific deletion of Cdc42 decreased natural Tregs but increased effector T cells including Th17 cells. Notably, Cdc42-deficient Th17 cells became pathogenic associated with enhanced glycolysis and Cdc42-deficient Tregs became unstable associated with weakened glycolytic signaling. Inhibition of glycolysis in Cdc42-deficient Th17 cells diminished their pathogenicity and restoration of glycolysis in Cdc42-deficient Tregs rescued their instability. Intriguingly, Cdc42 deficiency in T cells led to exacerbated wasting disease in mouse models of colitis and Treg-specific deletion of Cdc42 caused early, fatal lymphoproliferative diseases. In summary, we show that Cdc42 is a bona fide regulator of peripheral tolerance through suppression of Th17 aberrant differentiation/pathogenicity and promotion of Treg differentiation/stability/function involving metabolic signaling and thus Cdc42 pathway might be harnessed in autoimmune disease therapy.

Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

“…We have previously shown that thymic deletion of Cdc42 beginning at an early stage of thymocyte development by LCK Cre impaired thymocyte development, peripheral CD4 + and CD8 + T cell homeostasis, and iTreg differentiation but enhanced CD4 + and CD8 + T cell activation and Th1/Th17 cell differentiation with no effect on Th2 cell . In this study, we show that post‐thymic deletion of Cdc42 by dLCK iCre had no effect on thymocyte development, CD4 + T cell homeostasis, CD8 + T cell activation, and Th1/Th17/iTreg differentiation, whereas it dampened CD8 + T cell homeostasis, CD4 + T cell activation and Th2 cell differentiation.…”

“…We have previously shown that thymic deletion of Cdc42 beginning at an early stage of thymocyte development by LCK Cre impaired thymocyte development, peripheral CD4 + and CD8 + T cell homeostasis, and iTreg differentiation but enhanced CD4 + and CD8 + T cell activation and Th1/Th17 cell differentiation with no effect on Th2 cell. [17][18][19] In this study, we show that post-thymic deletion of Cdc42 by dLCK iCre had no effect on thymocyte development, CD4 + T cell Our transcriptome analysis found that Cdc42-deficient Th2 cells had increased mRNA expression of STAT4, indicative of Th1 reprogramming, 1 and of Foxp3, indicative of Treg reprogramming. 3,11 However, we did not detect alterations in protein expression of Th1 cytokine IFN-γ and Foxp3 in Cdc42-deficient Th2 cells ( Figure S6D and E), suggesting that the increased mRNA expression of STAT4…”

“…Cdc42 has been shown to regulate actin cytoskeleton reorganization, cell migration, proliferation, survival and oncogenesis . By T cell‐specific Cdc42 deletion, we have recently found that Cdc42 promotes thymocyte development, peripheral T cell homeostasis and iTreg cells but suppresses T cell activation, Th1 and Th17 cell differentiation, with no effect on Th2 cells …”

“…[13][14][15][16] By T cell-specific Cdc42 deletion, we have recently found that Cdc42 promotes thymocyte development, peripheral T cell homeostasis and iTreg cells but suppresses T cell activation, Th1 and Th17 cell differentiation, with no effect on Th2 cells. [17][18][19] In this study, we aimed to investigate the physiological role of Cdc42 in Th2 cell differentiation and function. We achieved post-thymic deletion of Cdc42 and found that post-thymic deletion of Cdc42 inhibited Th2 differentiation with no effect on Th1, Th17 and iTreg cells.…”

T Cell Metabolism: A New Perspective on Th17/Treg Cell Imbalance in Systemic Lupus Erythematosus

“…Glycolysis deprivation was found to impair Th17 differentiation dramatically, while defective glycolysis supported the development of Treg cells. Replacement of glucose with galactose, treatment with 2-DG (an inhibitor of hexokinase, the first rate-limiting enzyme of glycolysis), and lack of HIF1α, Cdc42, ICER, and mTOR (crucial regulators of T cell glycolytic metabolism) all resulted in diminished Th17 development but enhanced Treg cell differentiation (16)(17)(18)(19)(20). Conversely, inhibition of fatty acid oxidation results in diminished differentiation to Th17 cells, but increased development of Tregs (21).…”