VISTA is a novel immune checkpoint receptor and ligand that regulates T-cell activation. We investigated the functional involvement of VISTA in periodontitis using LPS-induced periodontitis model. Treatment with an anti-VISTA monoclonal antibody (mAb) enhanced the LPS-induced TNFa and IL-1b expression in gingiva and alveolar bone resorption. We also investigated the functional involvement of VISTA in Th2 cell-mediated immune responses using an OVA-induced allergic asthma model. Treatment with the anti-VISTA mAb during allergen challenge, but not sensitization, significantly augmented AHR and BAL fluid eosinophilia. This treatment also increased the production of IL-5 and IL-13 in BAL fluid and the expression of IL-13 by CD4+ T cells in draining lymph nodes. These results suggest that VISTA is involved in the regulation of both LPS-induced immune responses and antigen specific Th2 cell generation, and regulates periodontitis pathology and asthmatic responses, respectively.