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Review
. 2021 Nov;41(11):391-406.
doi: 10.1089/jir.2021.0147.

Interleukin-35: Structure, Function and Its Impact on Immune-Related Diseases

Cheng Ye  1 , Hiroshi Yano  1   2 , Creg J Workman  1 , Dario A A Vignali  1   3   4
Affiliations
Review

Interleukin-35: Structure, Function and Its Impact on Immune-Related Diseases

Cheng Ye et al. J Interferon Cytokine Res. 2021 Nov.

Abstract

The balance between inflammatory and anti-inflammatory immune responses is maintained through immunoregulatory cell populations and immunosuppressive cytokines. Interleukin-35 (IL-35), an inhibitory cytokine that belongs to the IL-12 family, is capable of potently suppressing T cell proliferation and inducing IL-35-producing induced regulatory T cells (iTr35) to limit inflammatory responses. Over the past decade, a growing number of studies have indicated that IL-35 plays an important role in controlling immune-related disorders, including autoimmune diseases, infectious diseases, and cancer. In this review, we summarize the current knowledge about the biology of IL-35 and its contribution in different diseases, and we discuss the potential of and barriers to harnessing IL-35 as a clinical biomarker or immunotherapy.

Keywords: IL-35; autoimmune diseases; cancer; infection.

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Conflict of interest statement

The authors declare competing interests. D.A.A.V. and C.J.W. have submitted patents covering IL-35 that are pending or approved and are entitled to a share in the net income generated from licensing of these patent rights for commercial development. D.A.A.V.: cofounder and stock holder—Novasenta, Tizona, Trishula, and Potenza; stock holder—Oncorus, Werewolf, Apeximmune; patents licensed and royalties—Novasenta, Astellas, Tizona, BMS; scientific advisory board member—Tizona, Werewolf, F-Star, Bicara; consultant—Astellas/Potenza, BMS, Incyte, Almirall, G1 Therapeutics; research funding—BMS, Astellas/Potenza, Tizona, and Novasenta. All other authors have declared that no competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
IL-35 is a member of the promiscuous IL-12 family of cytokines and signaling receptors. Family members are categorized into 2 distinct subunit chain types based on their structural homology: alpha-chains (p19, p28, and p35) and beta-chains (p40 and Ebi3). Alpha-chains also belong to the IL-6 superfamily due to their conserved 4 alpha helix-bundle structure. Beta-chains show structural homology to IL-6Rα and are also members of the class I cytokine receptor family (homology based on tandem fibronectin type III domains and conserved WSXWS motif near cytokine binding site). Their physiological roles range from potent proinflammatory immune responses (IL-12/IL-23/IL-27/IL-39) to immune regulation [IL-27/IL-35/IL-30/(p40)2]. Ebi3, Epstein-Barr virus induced 3; IL, interleukin.
FIG. 2.
FIG. 2.
Summary of IL-35 responders and producers. IL-35 is produced by a wide range of immune cells, including Tregs, iTr35, Bregs, tolerogenic DCs, and macrophages, and they primarily mediate suppression on effector T cells and B cells. Bregs, regulatory B cells; DCs, dendritic cells; iTr35, IL-35-producing induced regulatory T cells; Tregs, regulatory T cells.
See this image and copyright information in PMC

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