Regulatory T cells (Tregsanergy ͉ Blimp-1 ͉ inflammatory bowel disease ͉ IL-10 ͉ type 1 regulatory T cells

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Autoantibodies induce various autoimmune diseases, including systemic lupus erythematosus (SLE). We previously described that CD4+CD25−LAG3+ regulatory T cells (LAG3+ Treg) are regulated by Egr2, a zinc-finger transcription factor required for the induction of T-cell anergy. We herein demonstrate that LAG3+ Treg produce high amounts of TGF-β3 in an Egr2- and Fas-dependent manner. LAG3+ Treg require TGF-β3 to suppress B-cell responses in a murine model of lupus. Moreover, TGF-β3- and LAG3+ Treg-mediated suppression requires PD-1 expression on B cells. We also show that TGF-β3-expressing human LAG3+ Treg suppress antibody production and that SLE patients exhibit decreased frequencies of LAG3+ Treg. These results clarify the mechanism of B-cell regulation and suggest therapeutic strategies.

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Interleukin-27 (IL-27) suppresses immune responses through inhibition of the development of IL-17 producing Th17 cells and induction of IL-10 production.We previously showed that forced expression of early growth response gene 2 (Egr-2), a transcription factor required for T-cell anergy induction, induces IL-10 and lymphocyte activation gene 3 expression and confers regulatory activity on CD4 + T cells in vivo. Here, we evaluated the role of Egr-2 in IL-27-induced IL-10 production. Among various IL-10-inducing factors, only IL-27 induced high levels of Egr-2 and lymphocyte activation gene 3 expression. Intriguingly, IL-27 failed to induce IL-10 in Egr-2-deficient T cells. IL-27-mediated induction of Prdm1 that codes B lymphocyte induced maturation protein-1, a transcriptional regulator important for IL-10 production in CD4 + T cells, was also impaired in the absence of Egr-2. Although IL-27-mediated IL-10 induction was dependent on both STAT1 and STAT3, only STAT3 was required for IL-27-mediated Egr-2 induction. These results suggest that IL-27 signal transduction through Egr-2 and B lymphocyte induced maturation protein-1 plays an important role in IL-10 production. Furthermore, Egr-2-deficient CD4 + T cells showed dysregulated production of IFN-γ and IL-17 in response to IL-27 stimulation. Therefore, Egr-2 may play key roles in controlling the balance between regulatory and effector cytokines.Keywords: Blimp-1 r Egr-2 r IL-10 r IL-27 r inducible regulatory T (Treg) cells r Prdm1 See accompanying Commentary by Vasanthakumar and KalliesAdditional supporting information may be found in the online version of this article at the publisher's web-site [3,4]. IL-10 is an anti-inflammatory cytokine which was initially described as a cytokine associated with Th2 cells that inhibits the production of IFN-γ by Th1 cells [5,6]. A number of reports have revealed that IL-10 suppresses cytokine production and proliferation of T cells [7,8] and inhibits the T-cell-stimulating capacity of APCs [9]. IL-10-deficient mice die with spontaneously developed inflammatory bowel disease [10].Interleukin-27 (IL-27), a member of the IL-12/IL-23 heterodimeric family of cytokines produced by APCs, is composed of two chains, p28 and EBV-induced gene 3 [11]. IL-27 induces the expansion of Th1 cells by activating the STAT1-mediated T-bet pathway [12], but IL-27Rα-deficient mice developed severe EAE with enhanced Th17-cell responses [13]. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th17 cells and induction of IL-10 production [14]. Recently, IL-27 has been identified as a differentiation factor for IL-10-producing Tr1 cells [15][16][17]. On the other hand, B lymphocyte induced maturation protein-1 (Blimp-1) (coded by Prdm1 gene), a zinc finger-containing transcriptional regulator that is well known to be a regulator of plasma cell differentiation, is also important for IL-10 production in naïve CD4 + T cells. Martins et al. [18,19] reported that Blimp-1-deficient CD4 + T cells proliferated more and produce...