We report that like other T cells cultured in the presence of transforming growth factor (TGF) β, Th17 cells also produce interleukin (IL) 9. Th17 cells generated in vitro with IL-6 and TGF-β as well as purified ex vivo Th17 cells both produced IL-9. To determine if IL-9 has functional consequences in Th17-mediated inflammatory disease, we evaluated the role of IL-9 in the development and progression of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The data show that IL-9 neutralization and IL-9 receptor deficiency attenuates disease, and this correlates with decreases in Th17 cells and IL-6–producing macrophages in the central nervous system, as well as mast cell numbers in the regional lymph nodes. Collectively, these data implicate IL-9 as a Th17-derived cytokine that can contribute to inflammatory disease.

Interleukin-9 (IL-9) has attracted renewed interest owing to the identification of its expression by multiple T helper (TH) cell subsets, including TH2 cells, TH9 cells, TH17 cells and regulatory T (TReg) cells. Here, we provide a broad overview of the conditions that are required for cells to produce IL-9 and describe the cellular targets and nature of the immune responses that are induced by IL-9.

Significance The discovery of V domain-containing Ig suppressor of T-cell activation (VISTA) as a novel immune-checkpoint regulator comes at an exciting time, as the field of cancer immunotherapy has made significant progress owing to the clinical success of targeting immune-checkpoint proteins such as cytotoxic T lymphocyte-associated antigen 4 and programmed death 1 and ligand. Recent studies also show the promise of monoclonal antibody-mediated VISTA targeting for enhancing antitumor immunity in murine tumor models. The current study demonstrates the spectrum of immune alterations upon genetic disruption of VISTA in mice in the context of self-tolerance as well as immune response against neoantigen. These results enhance the understanding of the immune-regulatory role of VISTA and form the foundation for designing future clinical applications that target VISTA in treating human diseases.

Fine-tuning the immune response and maintaining tolerance to self antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking CTLA-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the PD-1 and B7-H4 pathways in various disease states. Recently two new B7 family inhibitory ligands, VISTA and B7-H6 were identified. Here we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target.