CD4⁺CD25⁻LAG3⁺ regulatory T cells in humoral immunity

Abstract

Regulatory T cells (Tregs) are necessary for the maintenance of peripheral immune tolerance. These Tregs are divided into two main subsets: thymus‐derived Tregs and peripherally‐derived Tregs. As a thymus‐derived Treg subset, CD4+CD25+ Tregs (CD25+ Tregs) that express the transcription factor, Forkhead box P3 (Foxp3), have been extensively studied. Type 1 regulatory T cells are representative Foxp3‐independent peripherally‐derived Tregs that produce a large amount of the inhibitory cytokine, interleukin (IL)‐10, and suppress immune responses through IL‐10 production. Accumulating evidence has shown that lymphocyte activation gene 3 (LAG3) is a reliable cell surface marker for type 1 regulatory T cells. Peripherally‐derived CD4+CD25−LAG3+ Tregs (LAG3+ Tregs) produce a large amount of IL‐10 and suppress colitis in a mouse model in an IL‐10‐dependent manner. LAG3+ Tregs characteristically express transcriptional factor early growth response gene 2 (Egr2), and ectopic expression of Egr2 conferred a suppressive function to CD4+ T cells. Intriguingly, polymorphism of the EGR2 gene is associated with susceptibility to systemic lupus erythematosus characterized by a wide spectrum of auto‐antibodies, and mice lacking Egr2 specifically in lymphocytes develop a lupus‐like autoimmune disease. We recently reported that Egr2‐expressing LAG3+ Tregs effectively suppress humoral immune responses in a transforming growth factor β3‐dependent manner. In addition, transforming growth factor β3 and IL‐10 synergistically regulate Toll‐like receptor‐mediated humoral immune responses. In the present review, we focus on the role of LAG3+ Tregs in humoral immunity, and also discuss its therapeutic potential for the treatment of autoimmune diseases.

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

“…LAG3 + cTregs and LAG3 + uTregs are considered Treg subsets possessing the ability to produce a large amount of IL-10 and regulate immune responses in different experimental and clinical settings 17 – 21 . To determine if these aberrant Tregs in patients with severe COVID-19 associate with an immune suppressive capability, we measured the level of suppressive effector molecule LAG3 + within cTregs/uTregs.…”

Decreased mRNA expression level of FOXP3 correlate with TNF-α in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis patients: a case control study

“…Presence of rheumatoid factor (RF) autoantibodies and anticitrullinated protein antibodies (ACPAs) are important in the diagnosis of RA but few patients are seronegative for these, and some patients in healthy control groups can show the presence of RF 7–10. The etiology of RA is unknown; however, a subset of T cells known as CD4 + CD25 + T regulatory (Treg) cells are involved in the modulation of the immune system, which regulates peripheral self-tolerance and controls immune responses of autoantibodies in various autoimmune diseases including RA 11–13…”

“…[7][8][9][10] The etiology of RA is unknown; however, a subset of T cells known as CD4 + CD25 + T regulatory (Treg) cells are involved in the modulation of the immune system, which regulates peripheral self-tolerance and controls immune responses of autoantibodies in various autoimmune diseases including RA. [11][12][13] The Treg cells with CD4 + CD25 + forkhead box P3 (FOXP3 + ) phenotype inhibit the pathogenic T cells and play crucial roles in immune regulation against self-antigens. 14 Demethylation at FOXP3 locus is one of the mechanisms of Treg cell regulation that maintains its phenotype and stability.…”