Abstract
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+CD25+ Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor Foxp3 is well known as a master regulatory gene for the development and function of CD4+CD25+ 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+CD25−LAG3+ Tregs (LAG3+ Tregs) develop in the periphery and produce a large amount of IL-10. LAG3+ Tregs characteristically express the early growth response gene 2 (Egr2), a zinc-finger transcription factor, and exhibit its suppressive activity in a Foxp3-independent manner. Although Egr2 was known to be essential for hindbrain development and myelination of the peripheral nervous system, recent studies revealed that Egr2 plays vital roles in the induction of T cell anergy and also the suppressive activities of LAG3+ Tregs. Intriguingly, forced expression of Egr2 converts naive CD4+ T cells into IL-10-producing Tregs that highly express LAG3. Among the four Egr gene family members, Egr3 is thought to compensate for the function of Egr2. Recently, we reported that LAG3+ Tregs suppress humoral immune responses via transforming growth factor β3 production in an Egr2- and Egr3-dependent manner. In this review, we focus on the role of Egr2 in Tregs and also discuss its therapeutic potential for the treatment of autoimmune diseases.
Highlights
Autoimmunity can cause a broad range of human diseases
These observations indicate that Lymphocyte activation gene 3 (LAG3) and CD49b are phenotypic markers of IL-10-producing, Forkhead box P3 (Foxp3)-independent, extrathymically induced CD4+ Tregs that play a major role in regulating the activity of the immune system [39]
We previously showed that adoptive transfer of IL-10-transduced T cells from chicken OVA-specific T cell receptor (TCR) transgenic DO11.10 mice ameliorated methylated bovine serum albumin (BSA)-induced arthritis when the arthritic joint was co-injected with OVA in addition to methylated BSA without impairing the systemic immune response to the antigen
Summary
Autoimmunity can cause a broad range of human diseases. This pathology is observed in at least 5% of the general population [1]. In 2009, we identified a Foxp3-independent IL-10-producing Treg subset, i.e., CD4+CD25−Foxp3− T cells These cells characteristically express both the lymphocyte activation gene 3 (Lag3) and the transcription factor early growth response gene 2 (Egr2) [13]. Lag mRNA is expressed on CD4+CD25+Foxp3+ Tregs [37], LAG3 protein was hardly detected on the cell surface of CD4+CD25+ Tregs [38] These observations indicate that LAG3 and CD49b are phenotypic markers of IL-10-producing, Foxp3-independent, extrathymically induced CD4+ Tregs that play a major role in regulating the activity of the immune system [39]. PD-1 ligand, and TGF-β3 enhanced PD-1 expression by stimulated B cells These observations indicate that TGF-β3 produced by LAG3+ Tregs plays a major role in the maintenance of humoral immune tolerance. Egr expressed in CD4+ T cells has an integral role in a broad range of immunological balances
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