VISTA Non-redundantly Regulates Proliferation and CD69low γδ T cell Accumulation in the Intestine in Murine Sepsis.

ABSTRACT

Sepsis is a dysregulated systemic immune response to infection that is responsible for ∼35% of in-hospital deaths at a significant fiscal health care 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 35-45 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 Tregs to prevent overt inflammation/pathology. In this study, we hypothesized that Jurkatfoxp3 T cells non-redundantly 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 sCD40L 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.