From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines

Abstract

Feedback regulatory circuits provided by regulatory T cells (T(reg) cells) and suppressive cytokines are an intrinsic part of the immune system, along with effector functions. Here we discuss some of the regulatory cytokines that have evolved to permit tolerance to components of self as well as the eradication of pathogens with minimal collateral damage to the host. Interleukin 2 (IL-2), IL-10 and transforming growth factor-β (TGF-β) are well characterized, whereas IL-27, IL-35 and IL-37 represent newcomers to the spectrum of anti-inflammatory cytokines. We also emphasize how information accumulated through in vitro as well as in vivo studies of genetically engineered mice can help in the understanding and treatment of human diseases.

Figure 1

The dialog between T_reg cells and DCs. (a) T_reg cells can inhibit the priming of effector T cells by preventing DC maturation through cell surface signaling by CTLA-4, PD-1 or LAG3 or by killing DCs through the secretion of granzymeps. After being stimulated by DCs, T cells can secrete latent TGF-β, which is activated by α_Vβ₈ expressed on the surface of DCs. The activated TGF-β can now signal DCs and other cell types. (b) DCs can induce the differentiation of T_reg cells. DCs activated by microbes or by ligation of certain surface molecules such as DC asialoglycoprotein receptor (DC-ASGPR) secrete either IL-27 or IL-10, which induce T cells to produce IL-10 (Tr1 cell). A subset of DCs secrete retinoic acid (RA) and TGF-β, which induce the differentiation of T cells into T_reg cells. MHC, major histocompatibility complex.

Figure 2

The dual roles of TGF-β in tolerance and immunity. TGF-β inhibits T_H1 cells, T_H2 cells and cytotoxic T lymphocytes (CTL), whereas it induces, in combination with other cytokines, the differentiation of T_reg cells and T_H17 cells. TGF-β together with IL-10 or IL-21 induces CD40-activated B cells to switch into IgA⁺ B cells, possibly with the help of T_H17 cells.

Figure 3

Members of the IL-12 family. IL-12 and IL-23 share the β-chain p40 (IL-12β), whereas IL-27 and IL-35 share the β-chain EBI3. IL-12 and IL-35 share the p35 α-chain, whereas IL-23 and IL-27 have unique α-chains. IL-12 and IL-23 are disulfide-linked heterodimers, whereas IL-27 and IL-35 lack the disulfide linkage.