Type 1 regulatory T cells (Tr1) in autoimmunity

Abstract

The ability of IL-10 producing Type 1 regulatory T cells (Tr1) to restrain the activation of effector immune cells during autoimmune responses underscores their essential role in maintaining immune tolerance. While mouse studies have demonstrated that increasing the numbers and/or function of Tr1 cells could improve the course of autoimmune diseases, the inability to generate Tr1 cells in vitro in large numbers has hampered identification of the molecular mechanisms responsible for their differentiation. Interleukin-27 (IL-27), a member of the IL-12 heterodimeric cytokine family, was identified as an important cytokine that suppresses effector T(H)17 cells and promotes the generation of Tr1 cells. Tr1 cells dampen autoimmunity and tissue inflammation partly through their secretion of the immunosuppressive cytokine IL-10. Here we review the molecular mechanisms involved in IL-27-induced Tr1 cell differentiation, with a focus on the role of two transcription factors, the aryl hydrocarbon receptor (AhR) and c-Maf. We also discuss how ligands that bind to AhR and affect the biology of IL-27-induced Tr1 cells can be exploited as a therapeutic approach to alleviate human autoimmune diseases.

Figure 1. Molecular mechanisms governing the induction of IL-27-induced Tr1 cells

Three different pathways are induced by IL-27 during Tr1 cell differentiation. IL-27 drives the expression of the transcription factors c-Maf and AhR, which bind together to transactivate the Il21 and Il10 promoters. IL-21 maintains Maf and AhR expression, while IL-10 is essential for the suppressive function of Tr1 cells (Upper panel). IL-27-induced AhR, alone or with an unknown cofactor, promotes Granzyme-B expression that mediates the contact-dependent suppressive activity of Tr1 cells (middle panel). Finally IL-27 promotes T-bet expression that results in IFN-γ secretion. IFN-γ then acts on DCs to enhance IL-27 expression and further supports Tr1 cell differentiation (lower panel).

Figure 2. IL-27 induces Granzyme B expression

RNA isolated from naïve CD4⁺CD44^loCD62L^hiCD25^- cells differentiated with IL-27 (25ng/ml) (Tr1) or without (T_H0) in the presence of anti-CD3 and anti-CD28 antibodies (2ug/ml) was subjected to quantitative real-time PCR amplification relative to the expression of mRNA encoding β-actin to examine expression of Il10 (left panel) and Gzmb (right panel) Il10 at different time points following activation.

Figure 3. Pharmacologic tools to support the differentiation of IL-27-induced Tr1 cells

Different treatments induce IL-27 secretion from dendritic cells (left panel) that will in turn enhance the development of Tr1 cells, resulting in the resolution of autoimmune inflammation. TLR stimulation with Poly I:C or LPS will activate TRIF, leading to endogenous type I IFN secretion. Endogenous type I IFN or exogenous treatment with IFN-β signals through their receptor IFNAR and enhance IL-27 expression. Statins, Galectin-1 as well as Foxp3⁺ induced Tregs promote IL-27 secretion through yet unknown mechanisms. IL-27 induces c-Maf and AhR expression in Tr1 cells (right panel). AhR ligands bind to the cytoplasmic AhR and both translocate into the nucleus. These newly formed complexes enhance the expression of Granzyme B and bind to c-Maf to transactivate Il10 and Il21 promoters.