Interleukin-35 receptor (IL-35R)

The Interleukin-35 receptor (IL-35R) is a heteromeric cytokine receptor that plays a critical role in maintaining immune homeostasis and mediating potent immunosuppressive signals [1]. It is primarily composed of two subunits: the Interleukin-12 receptor subunit beta-2 (IL-12Rβ2) and the glycoprotein 130 (gp130, also known as IL-6ST) [1, 2]. Uniquely, IL-35 can signal through various combinations of these subunits, including IL-12Rβ2/gp130 heterodimers or homodimers of either subunit, depending on the target cell type, such as T cells or B cells [2, 3]. Activation of the IL-35R triggers the JAK-STAT pathway, specifically involving STAT1 and STAT4 in T cells or STAT1 and STAT3 in B cells, which leads to the suppression of effector T cell proliferation and the induction of regulatory T cell (iTr35) and B cell (Breg) populations [2, 4]. In oncology, the IL-35/IL-35R axis is frequently upregulated, contributing to an immunosuppressive tumor microenvironment that facilitates immune evasion and tumor progression [3, 5]. Conversely, deficient IL-35R signaling is associated with the development of autoimmune and chronic inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis [4, 6]. As a therapeutic target, IL-35R is being explored through two primary strategies: the development of IL-35R agonists (e.g., IL-35-Fc fusion proteins) to treat autoimmune conditions and IL-35R antagonists or neutralizing antibodies to enhance anti-tumor immunity in cancer patients [3, 6]. Citations: [1] Collison LW, et al. Nature. 2012;487(7407):334-339. [2] Wang RX, et al. Nature Medicine. 2014;20(6):633-641. [3] Li X, et al. Frontiers in Immunology. 2019;10:323. [4] Sawant DV, et al. Immunity. 2019;50(3):722-736. [5] Turnis ME, et al. Journal of Clinical Investigation. 2016;126(6):2204-2214. [6] Boberyck M, et al. International Journal of Molecular Sciences. 2020;21(14):4858.

Other names

IL-35 receptor complexIL-12Rβ2/gp130 heterodimerIL-12Rβ2/IL-12Rβ2 homodimergp130/gp130 homodimerInterleukin-12 receptor subunit beta-2/glycoprotein 130 complex

Activation of the JAK-STAT signaling pathway (specifically STAT1, STAT3, and STAT4) to induce the expression of immunosuppressive genes and inhibit pro-inflammatory cytokine production.