Person:

Wu, Chuan

Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation. CD4+ T cells from PROCR low expressor mutant mice readily differentiated into Th17 cells, whereas addition of the PROCR ligand, activated protein C, inhibited Th17 differentiation in vitro. In addition, PROCR acted as a negative regulator of Th17 pathogenicity in that it down-regulated expression of several pathogenic signature genes, including IL-1 and IL-23 receptors. Furthermore, T cell–specific deficiency of PROCR resulted in the exacerbation of experimental autoimmune encephalomyelitis (EAE) and higher frequencies of Th17 cell in vivo, indicating that PROCR also inhibits pathogenicity of Th17 cells in vivo. PROCR thus does not globally inhibit Th17 responses but could be targeted to selectively inhibit proinflammatory Th17 cells.

RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.

Regulatory T cells (Treg cells) play a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis1,2. Transcriptional programming of regulatory mechanisms facilitates Treg cell functional activation in the prevention of diverse types of inflammatory responses3,4. How Treg cells orchestrate their homeostasis and interplay with environmental signals remains poorly understood. Here we show that liver kinase B1 (LKB1) programs proper metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1, and TNF receptor (TNRF) superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signaling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signaling for the proper control of PD-1 and TNFR proteins. Blockade of PD-1 activity reinvigorated the suppressive capability of LKB1-deficient Treg cells in the repression of TH2 responses and the interplay with thymic stromal lymphopoietin (TSLP)-primed dendritic cells (DCs). Thus, Treg cells employ LKB1 signaling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.

SUMMARY A balance between Th17 and regulatory T (Treg) cells is critical for immune homeostasis and tolerance. Our previous work has shown Serum- and glucocorticoid-induced kinase 1 (SGK1) is critical for the development and function of Th17 cells. Here, we show that SGK1 restrains the function of Treg cells and reciprocally regulates development of Th17/Treg balance. SGK1 deficiency leads to protection against autoimmunity and enhances self-tolerance by promoting Treg cell development and disarming Th17 cells. Treg cell-specific deletion of SGK1 results in enhanced Treg cell-suppressive function through preventing Foxo1 out of the nucleus, thereby promoting Foxp3 expression by binding to Foxp3 CNS1 region. Furthermore, our data suggest that SGK1 also plays a critical role in IL-23R-mediated inhibition of Treg and development of Th17 cells. Therefore, we demonstrate that SGK1 functions as a pivotal node in regulating the reciprocal development of pro-inflammatory Th17 and Foxp3+ Treg cells during autoimmune tissue inflammation.