Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia

Abstract

Considerable attention has been paid to interleukin (IL)-35 because of its immunosuppressive effects in a variety of autoimmune diseases. IL-35, a recently identified cytokine of the IL-12 family, is a negative regulatory factor secreted by IL-35-inducible regulatory T cells (iTr35 cells) and the recently reported regulatory B cells (B_reg cells). Four biological effects of IL-35 have been discovered in vitro and in vivo: (i) suppression of T cell proliferation; (ii) conversion of naive T cells into iTr35 cells; (iii) downregulation of type 17 helper T (T_h17) cells; and (iv) conversion of B_reg cells into a B_reg subset that produces IL-35 and IL-10. IL-35 plays an important role in a variety of autoimmune diseases, such as rheumatoid arthritis, allergic asthma and systemic lupus erythematosus. Primary immune thrombocytopaenia (ITP), which is characterized by isolated thrombocytopaenia and mild mucocutaneous to life-threatening bleeding, is an autoimmune disease with complex dysregulation of the immune system. Both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells and cytokine imbalances have now been recognized to be important. This review summarizes the immunomodulatory effects of IL-35 and its role in the pathogenesis of ITP as mediated by T and B cells.

Keywords: IL-35-inducible regulatory T cells; Interleukin-35; primary immune thrombocytopaenia.

Figure 1.

Interleukin (IL)-12 family members, their corresponding receptors and regulation of downstream signalling pathways. If both IL-12Rβ2 and gp130 in T cells are absent, the inhibition of IL-35 would be completely eliminated; if only one of the two is missing, then the inhibition of IL-35 would be partially suppressed. As members of the IL-12 family, IL-12, IL-23, IL-27 and IL-35 are heterodimeric, sharing subunits and their corresponding receptors. Each member is composed of an α chain (p19, p28 or p35) and a β chain (p40 or Epstein–Barr virus-induced gene 3 [EBI3]) whose expression is regulated independently. Receptors for the IL-12 family cytokines also share subunits. The IL-35 receptor consists of IL-12Rβ2/gp130 heterodimer or homodimer. IL-12Rβ2 is a component of the IL-12 receptor, whereas gp130 is a component of the IL-27 receptor. Upon receptor binding, cytokines transmit their signals through activation of members of the Janus activating kinase (JAK) family and activation and nuclear translocation of signal transducer and activator of transcription (STAT) family members. The colour version of this figure is available at: http://imr.sagepub.com.

Figure 2.

Interleukin (IL)-35 regulates T and B cell-mediated pro-inflammatory and anti-inflammatory immune responses. IL-35 suppresses conventional T cells and promotes their conversion to IL-35-inducible regulatory T cells (iTr35 cells), which play a vital role in immune regulation as they inhibit various immune responses due to the suppressive effects of IL-35. IL-35 can contribute to the induction of iTr35 cells and regulatory B (B_reg) cell populations and induces anti-inflammatory effects via the inhibition of type 1 helper T (T_h1) cell, T_h2 cell and T_h17 cell responses. The black arrows indicate positive effects and the T-shaped end indicates negative effects. IFN, interferon; TNF, tumour necrosis factor. The colour version of this figure is available at: http://imr.sagepub.com.

Figure 3.

The effect of interleukin (IL)-35 on the pathogenesis of primary immune thrombocytopaenia (ITP) is mediated by T and B cells. B cells require the help of helper T (T_h) cells to efficiently develop into antibody-secreting plasma cells. CD8+ T cells have been shown to directly lyse platelets, induce platelet apoptosis and inhibit thrombopoiesis by megakaryocytes (MK). These responses are based on macrophages and dendritic cells (DC) phagocytizing platelet fragments and presenting them to T_h cells. Regulatory T (T_reg) and B cells (B_reg) are important regulators that keep both B- and T cell-mediated autoimmunity in check. IL-35 (an immunosuppressive cytokine) and IL-35-inducible regulatory T cells (iTr35 cells; a new regulatory T cell) can inhibit the proliferation and function of T_h1, T_h2 and T_h17 cells, suppress cytotoxic activity and promote T_reg and B_reg cells. The arrows indicate positive effects and the T-shaped ends indicate negative effects. PC, platelet-reactive plasma cells. The colour version of this figure is available at: http://imr.sagepub.com.