Abstract
The transcription factors Egr2 and 3 are essential for controlling inflammatory autoimmune responses of memory phenotype (MP) CD4 T cells. However, the mechanism is still unclear. We have now found that the Egr2+ subset (PD-1high MP) of MP CD4 T cells expresses high levels of checkpoint molecules (PD-1 and Lag3) and also markers of effector T cells (CXCR3 and ICAM-1). Egr2/3 are not required for PD-1high MP CD4 cell development but mediate a unique transcriptional programme that effectively controls their inflammatory responses, while promoting homeostatic proliferation and adaptive responses. Egr2 negative PD-1high MP CD4 T cells are impaired in homeostatic proliferation and adaptive responses against viral infection but display inflammatory responses to innate stimulation 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 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.
Highlights
Checkpoint molecules such as PD-1 and Lag3 on T cells are important for the control of autoimmune pathology (Zhang & Vignali, 2016)
Despite the suppressive function of the PD-1–PD-L1 pathway on TCR-mediated proliferation, recently it has been discovered that PD-1high memory phenotype (MP) CD4 T cells are pathogenic in Rheumatoid Arthritis (RA) and systemic lupus erythematosus (SLE) patients and are inflammatory and 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 in the steady state
We analysed the phenotype of Egr2+ and Egr2− MP CD4 T cells and found that Egr2+ MP CD4 T cells expressed high levels of the checkpoint molecules PD-1 and Lag3, as well as markers associated with effector-like T cells (CCR5, CXCR3, and ICAM-1) (Fig 1B)
Summary
Checkpoint molecules such as PD-1 and Lag on T cells are important for the control of autoimmune pathology (Zhang & Vignali, 2016). The transcription factors Egr and 3 are expressed in MP CD4 T cells in the steady 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) They were initially 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 expansion of effector T cells in response to viral infection (Miao et al, 2017). 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
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