Interleukin-35 as an Emerging Player in Tumor Microenvironment

Xue, Wenhua; Yan, Dan; Kan, Quancheng

Recently, Collison LW et al. concluded that signal transduction of IL-35 does overlap with IL-12 and IL-27 transduction as it relays the signals using IL-12Rβ2 and gp130, which corresponds with IL-12 and IL-27 respectively [14] . Signal transduction is further carried through activation of pSTAT1 by gp130 chain and pSTAT4 by IL-12Rβ2 chain of receptor. Collison et al. explains that because the IL-35 signal transduction is carried out through two different but independent routes involving STAT signaling, the absence of either one of these two IL-35R chains will not affect the suppressive functions of IL-35 on T cells. However complete deletion of both chains of the receptor resulted in the loss of suppressive IL-35 effects [14] . Though conversion of conventional T cells into iTr35 require the phosphorylation of both STAT1 and STAT4 from gp130 chain and IL-12Rβ2 chain respectively [29] . iTr35 has specific tolerance promoting capabilities in parasitic infections and tumors. It is thought to work independently of (forkhead box P3) Foxp3, IL-10, and TGF-β [30] . Hetrodiamerization of STAT1 and STAT4 leads to upregulation of EBI3 or P35 which ultimately helps convert conventional T cells into iTr35. However a human study found that IL-35 can activate STAT1 and STAT3 heterodimers in human CD4+ T cells [31] . The expression pattern of IL-35R varies within the human system [3, 29, 32] . IL-12Rβ2 chain is expressed predominantly in activated T cells, natural killer cells [33] and dendritic cells [34] . IL-35 signaling in B cells is carried via IL-12Rb2: WSX-1, which activates phosphorylation of STAT1 and STAT3 [35] . IL-35 performs two distinctively notable functions. It suppresses the conventional T cells proliferation and transforms the conventional T cells into Treg cell population which are termed as iTr35 as they act through IL-35 [36, 37] . It also suppresses immune responses via strengthening Treg development and inhibiting Th17 cells growth [38] [39] [40] ( Figure 2 ).