IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation  Wenjun Ouyang, Anne O’Garra  Immunity  Volume 50, Issue 4, Pages 871-891 (April 2019) DOI: 10.1016/j.immuni.2019.03.020 Copyright © 2019 Elsevier Inc. Terms and Conditions

Figure 1 IL-10 Family Cytokines There are nine cytokines in the IL-10 family, which signal through two β chain receptors paired with four α chain receptors. In addition, there is one soluble receptor antagonist, IL-22 BP, which specifically neutralizes the activity of IL-22. Immunity 2019 50, 871-891DOI: (10.1016/j.immuni.2019.03.020) Copyright © 2019 Elsevier Inc. Terms and Conditions

Figure 2 Regulation of IL-10 Expression in Myeloid Cells and T Cells (A) TLR pathways exert important roles in induction of IL-10 production from myeloid cells. Various bacteria and their products can induce the production of IL-10 in macrophages by activating multiple pathways, including TLR2-MSK-CREB and TPL-2-ERK pathways, which regulate the expression of IL-10, as well as type I IFNs. Type I IFNs promote the production of IL-10 and synergize with IL-10 in regulating downstream inflammatory responses. (B) c-Maf and Bhlhe40 inversely regulate IL-10 expression in T cells. c-Maf enhances IL-10 expression in various T helper subsets in a context-dependent manner. On the other hand, Bhlhe40 exerts an essential role in repressing IL-10 expression in Th1 and Th17 cells. Interestingly, c-Maf and Bhlhe40 may negatively regulate the expression of each other. Immunity 2019 50, 871-891DOI: (10.1016/j.immuni.2019.03.020) Copyright © 2019 Elsevier Inc. Terms and Conditions

Figure 3 The Regulation and Downstream Functions of IL-22 (A) AhR plays a certral role in the regulation of IL-22 in T cells and ILC3s. Microbiota can regulate IL-22 production through the modulation of AhR ligand. Many other cellular pathways, such as Notch, CD69 and LAT1, and PGE2 can all converge to the AhR pathway to influence the expression of IL-22. (B) Multiple downstream mechanisms of IL-22 mediate its regulation of innate and adaptive immunity and tissue homeostasis. IL-22 can induce various innate immune responses and tissue-protective and tissue-regenerative mechanisms locally. In addition, IL-22 can promote systemic immune responses by acting on liver and inducing various anti-microbial mechanisms, such as HPX, hepcidin, and C3. Immunity 2019 50, 871-891DOI: (10.1016/j.immuni.2019.03.020) Copyright © 2019 Elsevier Inc. Terms and Conditions

Figure 4 Immune Promoting and Suppressing Mechanisms of IL-10 in Cancer Immunotherapy There are at least three major mechanisms of IL-10 that can impact the outcome of IL-10 as an immunotherapeutic strategy. First, IL-10 processes immune-stimulating effect, especially on CD8 T cells, which may promote anti-tumor activities. Second, IL-10 suppresses antigen presentation by myeloid cells and inhibits the production of IFN-γ-promoting cytokines, especially IL-12, from these cells as well, which hinders the induction of strong anti-tumor immunity. Third, certain proinflammatory cytokines, such as IL-6 and IL-23 from myeloid cells, can facilitate tumor growth under chronic inflammation. The inhibitory effect of IL-10 on these cytokines may be beneficial in certain cancers. Immunity 2019 50, 871-891DOI: (10.1016/j.immuni.2019.03.020) Copyright © 2019 Elsevier Inc. Terms and Conditions