IL-9-producing invariant NKT cells protect against DSS-induced colitis in an IL-4-dependent manner

Abstract

Although the T-helper type 9 (Th9) subset has recently been revisited, interleukin (IL)-9-producing invariant natural killer T (iNKT) cells remain poorly characterized. Moreover, whether IL-9-producing iNKT cells regulate colitis is unknown. Here, we investigated functions of IL-9-producing iNKT cells in dextran sulfate sodium (DSS)-induced colitis. Wild-type (WT) mice attenuated colitis compared to Jα18(-/-) mice, which were restored by the adoptive transfer of WT, but not IL-4-deficient iNKT cells. IL-4-deficient iNKT cells failed to produce IL-9, which was reversed by recombinant IL-4. Furthermore, iNKT cells, pre-incubated with anti-CD3+CD28 monoclonal antibodies and IL-4+tumor growth factor (TGF)-β (IL-9(+) iNKT), suppressed colitis in Jα18(-/-) mice, whereas pre-incubated IL-4-deficient iNKT cells did not. IL-9 blockade reversed IL-9(+) iNKT cell-mediated colitis by increasing colonic IL-17A and interferon (IFN)-γ transcripts, but decreasing IL-9, IL-10, TGF-β, PU.1, IFN regulatory factor 4, and signal transducer and activator of transcription 5 in Jα18(-/-) mice. In conclusion, IL-9-producing iNKT cells protect against DSS-induced colitis through IFN-γ and IL-17A suppression, but IL-10 and TGF-β enhancement, depending on the IL-4 production by iNKT cells.

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty

“…Known pleiotrophy of certain cytokines in salvaged blood, such as IL-17A, IFN-γ and TNF-α, could have facilitated regenerative rather than proinflammatory processes, as they would have facilitated synthesis of the chemokines MCP-1/CCL2, MIP-1α/CCL3 and IL-8/CXCL8 [47]. Moreover, IL-9 and IL-10 would have facilitated wound healing by suppressing autoinflammatory reactions and excessive scarring [48][49][50].…”

IL-9 Expression by Invariant NKT Cells Is Not Imprinted during Thymic Development

“…The regulation of Th9 differentiation is not yet fully understood, but it is thought to rely on the balance of several transcription factors, including PU.1, BATF, IRF-4, and GATA-3 (35,42). Except for Gata3 mRNA, which also regulates development, survival, activation, and effector function of iNKT cells (25), the gene regulatory network more specific for the Th9 program, namely PU.1, BATF, and IRF-4, displayed a similar kinetic profile between iNKT and CD4 T cells, strongly suggesting that IL-9 expression is regulated through similar mechanisms in both cell types. Irf4 and Batf were the only genes exhibiting a heightened expression in iNKT cells, in comparison with ex vivo.…”

“…It was previously reported IL-9-producing iNKT cells can confer protection against DSS-induced colitis (25). Because iNKT cells showed an outstanding capacity of secreting elevated amounts of IL-9, and conventional Th9 CD4 T cells are known to contribute to allergic inflammation by promoting proliferation of mast cells and goblet cells, as well as influx and local maturation of eosinophils (37-39), we investigated whether iNKT cells could contribute to allergic airway inflammation.…”

“…NKT cells expressing non-classical functions have also been documented, including Foxp3 + regulatory NKT cells (16,17), follicular helper NKT cells (18)(19)(20)(21), and NKT cells secreting further types of cytokines, such as IL- 10 (22) and IL-9 (8,(23)(24)(25). Being the archetype cytokine of Th9 responses, IL-9 secretion by invariant (iNKT) cells has been investigated (25).…”

“…Being the archetype cytokine of Th9 responses, IL-9 secretion by invariant (iNKT) cells has been investigated (25). Not only were IL-9-producing iNKT cells identified in vivo, but also these cells were reported to confer protection against DSS-induced colitis (25).…”