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no. MP CD4 T cells are impaired in homeostatic proliferation and adaptive responses against viral contamination but display inflammatory responses to innate activation such as IL-12. PD-1high MP CD4 T cells have recently been implicated in rheumatoid arthritis pathogenesis, and we have now found that Egr2 expression is usually reduced in PD-1high MP CD4 T cells from patients with active rheumatoid arthritis compared with healthy controls. These findings demonstrate that Egr2/3 control the inflammatory responses of PD-1high MP CD4 T cells and maintain their adaptive immune fitness. Introduction Checkpoint molecules such as PD-1 and Lag3 on T cells are important for the control of autoimmune pathology (Zhang & Vignali, 2016). Antigen persistence, such as in chronic infections and tumours, can induce PD-1 and Lag3 expression which can lead to exhaustion of effector T cells (Wherry, 2011). In addition to its role in exhaustion, PD-1 is usually expressed in memory phenotype (MP), but not na?ve, CD4 T cells in the constant state and plays an important role in peripheral tolerance and the prevention of autoimmunity in mouse models (Lin et al, 2007; Thangavelu et al, 2011; Pauken et al, 2015). Lag3 is also expressed in MP CD4 T cells and is involved in regulation of homeostasis (Nakachi et al, 2017). However, despite the suppressive function of the PD-1CPD-L1 pathway on TCR-mediated proliferation, recently it has been discovered that PD-1high MP CD4 T cells are pathogenic in Rheumatoid Arthritis (RA) and systemic lupus erythematosus (SLE) patients and are not only inflammatory but also promote the responses of autoimmune B cells (Rao et al, 2017; Bocharnikov et al, 2019; Caielli et al, 2019; Zhang et al, 2019), indicating that regulatory mechanisms in these cells control their homeostasis FM19G11 in the constant state. The transcription factors Egr2 and 3 are expressed in MP CD4 T cells in FM19G11 the constant state and defects in these two molecules in T cells lead to inflammatory activation and the development of autoimmune symptoms (Zhu et al, 2008; Li et al, 2012; Morita et al, 2016). Although they were in the beginning implicated in inhibition of T-cell proliferation (Harris et al, 2004; Safford et al, 2005), Egr2/3 are not generic inhibitors of T-cell proliferation but are required for clonal growth of effector T cells in response to viral infection (Miao et al, 2017). Furthermore, Egr2 and 3 do not directly inhibit the proliferation of tolerant T Rabbit polyclonal to Chk1.Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA.May also negatively regulate cell cycle progression during unperturbed cell cycles.This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. cells, but effectively control inflammatory responses of both effector and tolerant T cells (Omodho et al, 2018). We found that Egr2/3 are only expressed in a subset of MP CD4 T cells, but the phenotypes and function of Egr2/3 expressing MP CD4 T cells are largely unknown. Here, we show that Egr2/3 are stably expressed in a subset of MP CD4 T cells which express high levels of PD-1 and Lag3 (PD-1high MP CD4 T cells) as well as activation markers. Egr2/3 are not required for the development of PD-1high MP CD4 T cells but instead are essential for their homeostatic proliferation as well as control of their inflammatory function in the constant state. These functions of Egr2/3 in PD-1high MP CD4 T cells are required for the maintenance of a diverse repertoire of MP T cells, which is usually important for adaptive responses against viral contamination. Egr2 regulates the expression of genes in PD-1high MP CD4 T cells involved in proliferation, metabolism, and homeostasis as well as inflammation. In the absence of Egr2 and 3, PD-1high MP CD4 T cells displayed impaired homeostatic proliferation and adaptive responses but skewed TCR repertoires and innate-like inflammatory function. We also found that Egr2 is usually expressed in PD-1high MP CD4 T cells in human peripheral blood and its expression is usually impaired in patients with active RA. Thus, the homeostasis of PD-1high MP CD4 T cells, regulated by Egr2/3, FM19G11 is usually.