A Novel Role for IL-27 in Mediating the Survival of Activated Mouse CD4 T Lymphocytes

Abstract

IL-27, an IL-12 family cytokine, has pleiotropic functions in the differentiation and expansion of CD4+ T cell subsets. Here, we discovered a novel function of IL-27. CD4+CD45RBhigh T cells from mice deficient for the α chain of IL-27 receptor failed to induce colitis in Rag−/− recipients, because of an inability of activated donor cells to survive. Interestingly, IL-27 was indispensable for prevention of colitis by regulatory T cells, also because of a defect in long-term cell survival. IL-27 affected the survival of activated T lymphocytes, rather than promoting cell proliferation, by inhibiting Fas-mediated activation-induced T cell death, acting through the STAT3 signaling pathway. The addition of IL-27 during activation resulted in an increased cell number, which was correlated with decreased activation of both caspases 3 and 8. This pro-survival effect was attributed to downregulation of FasL, as well as to the induction of the anti-apoptotic protein cFLIP. While activation induced cell death is an important mechanism for the maintenance of immunological homeostasis, protection of lymphocytes from excessive cell death is essential for effective immunity. Our data indicate that IL-27 plays a crucial role in the inhibition of activation-induced cell death, thereby permitting antigen-driven T cell expansion.

Recruitment of IL-27-Producing CD4+ T Cells and Effect of IL-27 on Pleural Mesothelial Cells in Tuberculous Pleurisy

“…Moreover, IFN-c could induce significantly PMC apoptosis by activating STAT1 signaling, whereas IL-27 not only decreased PMC apoptosis, but also prevented completely the IFN-cinduced apoptosis by activating STAT3 signaling. Our results were consistent with those reported by Kim and colleagues that IL-27 prevented T cells from apoptosis through a STAT3-dependent mechanism [16].…”

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…In light of the highly pleiotropic nature of IL-27 signaling in both inflammation and immune regulation, we uncovered a surprisingly consistent and dramatic effect of IL-27 on the magnitude of T-cell responses across a spectrum of vaccine adjuvant-elicited cellular responses. Our data join only a few existing publications (9,19,42) directly demonstrating in vivo a direct positive role of IL-27R signaling in nonregulatory T-cell phenotypes. Many examples exist in the literature with indirect evidence of a positive role for IL-27 in enhancing CD8 T-cell responses, particularly in cancer therapy (17,18), but rarely is the direct effect of IL-27 on T cells examined.…”

“…Encounters that produce longstanding cellular immunity induce a balanced cytokine milieu, using both stimulatory (STAT1) and suppressive (STAT3) signaling pathways. IL-27 is a member of the IL-12 family of cytokines and, via its signaling through both STAT1 and STAT3 (8)(9)(10)(11)(12), contributes to a spectrum of T-cell functions and phenotypes.…”

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…This is in contrast to a study describing that cDC-derived Opn induces Th17 responses mainly through the inhibition of IL-27 in the experimental autoimmune encephalomyelitis (EAE) model (17). However, a recent report demonstrates that IL-27 is detrimental for colitis because it mediates survival of activated CD4 + T cells, resulting in enhanced disease severity (56). In addition, IL-27 inhibits Foxp3 induction in CD4 + T cells in vitro (57).…”