AUTHOR=Okamura Tomohisa , Yamamoto Kazuhiko , Fujio Keishi 

TITLE=Early Growth Response Gene 2-Expressing CD4+LAG3+ Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00340

DOI=10.3389/fimmu.2018.00340

ISSN=1664-3224

ABSTRACT=<p>Regulatory T cells (Tregs) are necessary for the maintenance of immune tolerance. Tregs are divided into two major populations: one is thymus derived and the other develops in the periphery. Among these Tregs, CD4<sup>+</sup>CD25<sup>+</sup> Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor <italic>Foxp3</italic> is well known as a master regulatory gene for the development and function of CD4<sup>+</sup>CD25<sup>+</sup> Tregs. On the other hand, peripheral Tregs consist of distinct cell subsets including Foxp3-dependent extrathymically developed Tregs and interleukin (IL)-10-producing type I regulatory T (Tr1) cells. Lymphocyte activation gene 3 (LAG3) and CD49b are reliable cell surface markers for Tr1 cells. CD4<sup>+</sup>CD25<sup>−</sup>LAG3<sup>+</sup> Tregs (LAG3<sup>+</sup> Tregs) develop in the periphery and produce a large amount of IL-10. LAG3<sup>+</sup> Tregs characteristically express the early growth response gene 2 (<italic>Egr2</italic>), a zinc-finger transcription factor, and exhibit its suppressive activity in a Foxp3-independent manner. Although <italic>Egr2</italic> was known to be essential for hindbrain development and myelination of the peripheral nervous system, recent studies revealed that <italic>Egr2</italic> plays vital roles in the induction of T cell anergy and also the suppressive activities of LAG3<sup>+</sup> Tregs. Intriguingly, forced expression of <italic>Egr2</italic> converts naive CD4<sup>+</sup> T cells into IL-10-producing Tregs that highly express LAG3. Among the four <italic>Egr</italic> gene family members, <italic>Egr3</italic> is thought to compensate for the function of <italic>Egr2</italic>. Recently, we reported that LAG3<sup>+</sup> Tregs suppress humoral immune responses <italic>via</italic> transforming growth factor β3 production in an Egr2- and Egr3-dependent manner. In this review, we focus on the role of <italic>Egr2</italic> in Tregs and also discuss its therapeutic potential for the treatment of autoimmune diseases.</p>