Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity

Abstract

Cytokines play a major role in maintaining lymphocyte homeostasis under both steady-state and inflammatory conditions. Unregulated lymphocytes in steady-state conditions can lead to autoimmunity, whereas during inflammation they can cause excessive tissue damage. Regulatory cytokines function in combination with other environmental signals to properly modulate the function and the extent of lymphocyte activation. Many recent studies have highlighted the importance of regulatory cytokines in controlling the differentiation and function of lymphocytes under steady-state and inflammatory conditions, as well as minimizing tissue damage.

Figure 1. Under steady-state conditions, TGF-β and IL-10 maintain peripheral and gut tolerance

A) In the periphery, T cells with low affinity for self antigens undergo homeostatic turn-over in response to self antigen and IL-7. TGF-β inhibits T cell activation and effector differentiation in response to self antigens, allowing a slow homeostatic proliferation of naïve T cells. B) In the gut, commensal bacteria/flora and food antigens are constantly sampled by intestinal DCs. Tolerogenic CD103⁺ DCs produce RA which inhibits effector cytokine production by CD4⁺CD44⁺ T cells. In the absence of effector cytokines and in the presence of high concentrations of TGF-β, naïve CD4⁺ T cells are converted into Foxp3⁺ iTregs that produce TGF-β and IL-10. IL-10 produced by IELs and iTregs regulates activation of intestinal lymphocytes, and reduces the expression of IL-12 and downregulates costimulatory molecules on macrophages.

Figure 2. The role of TGF-β, IL-10 and IL-22 during inflammation

Upon recognition of pathogen-associated molecular patterns (PAMPs), such as LPS, APCs become activated and express IL-10. This innate-derived IL-10 in turn down-modulates effector T cell responses, as well as the pro-inflammatory responses of APCs themselves. Naive CD4⁺ T cells when activated in the presence of low concentrations of TGF-β and inflammatory cytokines, such as IL-6, leads to the generation of Th17 cells. Th17 cells comprise a heterogeneous population of cells that express different types and amounts of the prototypical cytokines, which include IL-10, IL-22, and IL-17. Although depicted here as single producers, co-expression of these cytokines has been observed. In the absence of IL-23, this differentiation leads to a population of Th17 cells that express IL-10. IL-10 is important for down-modulating the responses of effector T cells, as well as their proliferation, thereby preventing excessive tissue damage from harmful IFNγ and granzymes, as well as Fas-FasL-mediated apoptosis. In a more direct manner, IL-22 also protects tissues from damage during inflammation. IL-22 directly stimulates anti-apoptotic and proliferative programs in many kinds of epithelial cells, such as hepatocytes or those cells lining the colon, allowing for tissue maintenance and repair during inflammation. IL-22 is also expressed by NK cells upon stimulation with IL-23. By contrast, IL-23 stimulation combined with low concentrations of TGF-β and IL-6 leads to a population of Th17 cells that express greater levels of IL-17. In some inflammatory settings, these pro-inflammatory cells appear to cause tissue damage, perhaps through recruitment of PMNs.