Interleukin 35: Critical regulator of immunity and lymphocyte-mediated diseases

Abstract

Cytokines coordinate the activities of innate and adaptive immune systems and the Interleukin 12 (IL-12) family of cytokines has emerged as critical regulators of immunity in infectious and autoimmune diseases. While some members (IL-12 and IL-23) are associated with the pathogenesis of chronic inflammatory diseases, others (IL-27 and IL-35) mitigate autoimmune diseases. Unlike IL-12, IL-23 and IL-27 that are produced mainly by antigen presenting cells, IL-35 is predominantly secreted by regulatory B (i35-Bregs) and T (iTR35) cells. The discovery that IL-35 can induce the conversion or expansion of lymphocytes to regulatory B and T cells has considerable implications for therapeutic use of autologous regulatory B and T cells in human diseases. Although our current understanding of the immunobiology of IL-35 or its subunits (p35 and Ebi3) is still rudimentary, our goal in this review is to summarize what we know about this enigmatic cytokine and its potential clinical use, particularly in the treatment of CNS autoimmune diseases.

Keywords: Adoptive B cell therapy; Autoimmune diseases; Breg; Cytokine therapy; IL-12 family cytokines; Interleukin 35; Regulatory B cells; i35-Breg; iTR35.

Figure 1

The IL-12 family of heterodimeric cytokines. Each member is comprised of an α-subunit (IL-12p19, IL-12 p35, IL-27p28) homologous to classic 4-helix bundle type 1 cytokines (e.g. IL-6) and a β-subunit (IL-12p40, Ebi3) structurally related to the soluble IL-6 receptor (IL-6Rα). Upon binding to cognate receptors (IL-12Rβ1, IL-12Rβ2, IL-23R, IL-27Rα, or gp130), receptor-associated Janus kinases (Jak1, Jak2, Tyk2)) are activated, providing phosphotyrosine-docking sites that recruit specific members of the STAT (signal transducers and activators of transcription) family of transcription factors.

Figure 2

Analysis of FPLC fractions of supernatant from insect cells expressing mouse recombinant IL-35 (rIL-35) by SDS-PAGE. Numbers (16 to 33) indicate fractions collected during size exclusion chromatography. The arrows indicate the presence of p35/Ebi3 (rIL-35), p35:p35 and Ebi3:Ebi3 homodimers as well as p35 and Ebi3 monomers in the preparation after passage through the first gel filtration column. For all functional and animal studies, the rIL-35 was purified by affinity chromatography using Ni-NTA followed by at least two consecutive cycles of gel filtration using Sephacryl S-200 HR Hiprep 16/60 and Superose-6 HR 10/30.

Figure 3

Role of IL-35-producing B (i35-Breg) and T (iTR35) cells in the regulation of hematopoietic cells.