Regulation of adaptive immunity; the role of interleukin-10

Abstract

Since the discovery of interleukin-10 (IL-10) in the 1980s, a large body of work has led to its recognition as a pleiotropic immunomodulatory cytokine that affects both the innate and adaptive immune systems. IL-10 is produced by a wide range of cell types, but for the purposes of this review we shall focus on IL-10 secreted by CD4(+) T cells. Here we describe the importance of IL-10 as a mediator of suppression used by both FoxP3(+) and FoxP3(-) T regulatory cells. Moreover, we discuss the molecular events leading to the induction of IL-10 secretion in T helper cell subsets, where it acts as a pivotal negative feedback mechanism. Finally we discuss how a greater understanding of this principle has allowed for the design of more efficient, antigen-specific immunotherapy strategies to exploit this natural phenomenon clinically.

Keywords: T helper cells; allergy; autoimmunity; cytokines; immune regulation; immunotherapy; interleukin-10; regulatory T cells.

Figure 1

In response to IL-6, TGF-β, and TCR stimulation naïve CD4⁺ cells upregulate RoRγt and c-Maf transcription factors and develop into T_H17 polarized naïve CD4⁺ cells which secrete IL-17 and IL-10 (McGeachy et al., 2007). In the presence of IL-6, TGF-β, IL-23, and TCR stimulation, naïve CD4⁺ cells differentiate into effector T_H17 cells which express RoRγt and secrete IL-17 and GM-CSF (McGeachy et al., 2009). In response to Staphylococcus aureus, effector T_H17 cells develop into CCR6⁺ CCR4⁺ memory cells which secrete IL-17A and IL-10; *however, it is unclear if c-Maf regulates IL-10 in these cells (Metzler and Wraith, ; Zielinski et al., 2012). T_H17 cells express the IL-10 receptor and can therefore self-regulate (Stumhofer et al., ; Huber et al., 2011). IL-1β can down regulate IL-10 expression from both T_H17 polarized naïve CD4⁺ cells and T_H17 memory cells (Zielinski et al., 2012).

Figure 2

In response to either IL-12 or IL-4 and TCR stimulation naïve CD4⁺ T cells will upregulate T-bet or GATA3 transcription factors respectively. Differentiation of naïve CD4⁺ t cells into T_H1/T_H2 lineages is based on T-bet/GATA3 transcription factor expression (Ouyang et al., ; Lucas et al., 2003). Upon repeated chronic TCR stimulation T_H1 and T_H2 cells express IL-10 (Gabryšová et al., ; Xu et al., 2009). In T_H1 cells, IL-10 expression is regulated by NFIL3 and correlates with c-Maf expression (Kim et al., ; Saraiva et al., 2009). In T_H2 cells, IL-10 expression is regulated by NFIL3 (Motomura et al., 2011). IL-10 secreted by T_H1/T_H2 cells can inhibit further naïve CD4⁺ differentiation by inhibiting IL-12/IL-4 and DC function (Moore et al., ; Taylor et al., 2007, 2009).

Figure 3

In T_H1 cells IL-10 expression is induced by IL-12-STAT4 and IL-27-STAT1 pathways, possibly through c-Maf and NFIL3 (Saraiva et al., 2009). In T_H2 cells IL-10 expression is induced by IL-4-STAT6 through GATA3 (imprinting and chromatin modification) and NFIL3 (Shoemaker et al., ; Motomura et al., 2011). In T_H17 cells IL-10 expression is induced by IL-6/TGF-β-STAT3 through c-Maf (Xu et al., 2009). In Tr1 cells, IL-10 is induced by IL-27 and AhR through induction of C-Maf (Pot et al., ; Apetoh et al., 2010). *c-Maf is correlated with IL-10 expression in T_H1 cells (Saraiva et al., 2009). In non-polarizing culture conditions, IL-10 expression is dependent on c-Maf (Kim et al., 1999). Whether c-Maf binds to the IL-10 locus in T_H1 cells is unknown. **NFIL3-deficient T_H1 cells do not express IL-10 on repetitive stimulation, but NFIL3 has not been observed bound to the IL-10 locus in T_H1 cells. (Motomura et al., 2011).