VISTA nonredundantly regulates proliferation and CD69low γδ T cell accumulation in the intestine in murine sepsis.

Sepsis is a dysregulated systemic immune response to infection i.e. responsible for ∼35% of in-hospital deaths at a significant fiscal healthcare cost. Our laboratory, among others, has demonstrated the efficacy of targeting negative checkpoint regulators (NCRs) to improve survival in a murine model of sepsis, cecal ligation and puncture (CLP). B7-CD28 superfamily member, V-domain immunoglobulin suppressor of T cell activation (VISTA), is an ideal candidate for strategic targeting in sepsis. VISTA is a 35 to 45 kDa type 1 transmembrane protein with unique biology that sets it apart from all other NCRs. We recently reported that VISTA-/- mice had a significant survival deficit post-CLP, which was rescued upon adoptive transfer of a VISTA-expressing pMSCV-mouse Foxp3-EF1α-GFP-T2A-puro stable Jurkat cell line (Jurkatfoxp3 T cells). Based on our prior study, we investigated the effector cell target of Jurkatfoxp3 T cells in VISTA-/- mice. γδ T cells are a powerful lymphoid subpopulation that require regulatory fine-tuning by regulatory T cells to prevent overt inflammation/pathology. In this study, we hypothesized that Jurkatfoxp3 T cells nonredundantly modulate the γδ T cell population post-CLP. We found that VISTA-/- mice have an increased accumulation of intestinal CD69low γδ T cells, which are not protective in murine sepsis. Adoptive transfer of Jurkatfoxp3 T cells decreased the intestinal γδ T cell population, suppressed proliferation, skewed remaining γδ T cells toward a CD69high phenotype, and increased soluble CD40L in VISTA-/- mice post-CLP. These results support a potential regulatory mechanism by which VISTA skews intestinal γδ T cell lineage representation in murine sepsis.