CD 4 + CD 25 − LAG 3 + regulatory T cells in humoral immunity

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, CD 4 + CD 25 + Tregs ( CD 25 + 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 ( LAG 3) is a reliable cell surface marker for type 1 regulatory T cells. Peripherally‐derived CD 4 + CD 25 − LAG 3 + Tregs ( LAG 3 + Tregs) produce a large amount of IL ‐10 and suppress colitis in a mouse model in an IL ‐10‐dependent manner. LAG 3 + Tregs characteristically express transcriptional factor early growth response gene 2 (Egr2), and ectopic expression of Egr2 conferred a suppressive function to CD 4 + T cells. Intriguingly, polymorphism of the EGR 2 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 LAG 3 + 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 LAG 3 + Tregs in humoral immunity, and also discuss its therapeutic potential for the treatment of autoimmune diseases.