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Immunol."],"abstract":"<jats:p>Sepsis is a systemic immune response to infection that is responsible for ~35% of in-hospital deaths and over 24 billion dollars in annual treatment costs. Strategic targeting of non-redundant negative immune checkpoint protein pathways can cater therapeutics to the individual septic patient and improve prognosis. B7-CD28 superfamily member<jats:underline>V<\/jats:underline>-domain<jats:underline>I<\/jats:underline>mmunoglobulin<jats:underline>S<\/jats:underline>uppressor of<jats:underline>T<\/jats:underline>cell<jats:underline>A<\/jats:underline>ctivation (VISTA) is an ideal candidate for strategic targeting in sepsis. We hypothesized that immune checkpoint regulator, VISTA, controls T-regulatory cells (T<jats:sub>reg<\/jats:sub>), in response to septic challenge, thus playing a protective role\/reducing septic morbidity\/mortality. Further, we investigated if changes in morbidity\/mortality are due to a T<jats:sub>reg<\/jats:sub>-mediated effect during the acute response to septic challenge. To test this, we used the cecal ligation and puncture model as a proxy for polymicrobial sepsis and assessed the phenotype of CD4<jats:sup>+<\/jats:sup>T<jats:sub>regs<\/jats:sub>in VISTA-gene deficient (VISTA<jats:sup>-\/-<\/jats:sup>) and wild-type mice. We also measured changes in survival, soluble indices of tissue injury, and circulating cytokines in the VISTA<jats:sup>-\/-<\/jats:sup>and wild-type mice. We found that in wild-type mice, CD4<jats:sup>+<\/jats:sup>T<jats:sub>regs<\/jats:sub>exhibit a significant upregulation of VISTA which correlates with higher T<jats:sub>reg<\/jats:sub>abundance in the spleen and small intestine following septic insult. However, VISTA<jats:sup>-\/-<\/jats:sup>mice have reduced T<jats:sub>reg<\/jats:sub>abundance in these compartments met with a higher expression of Foxp3, CTLA4, and CD25 compared to wild-type mice. VISTA<jats:sup>-\/-<\/jats:sup>mice also have a significant survival deficit, higher levels of soluble indicators of liver injury (i.e., ALT, AST, bilirubin), and increased circulating proinflammatory cytokines (i.e., IL-6, IL-10, TNF\u03b1, IL-17F, IL-23, and MCP-1) following septic challenge. To elucidate the role of T<jats:sub>regs<\/jats:sub>in VISTA<jats:sup>-\/-<\/jats:sup>sepsis mortality, we adoptively transferred VISTA-expressing T<jats:sub>regs<\/jats:sub>into VISTA<jats:sup>-\/-<\/jats:sup>mice. This adoptive transfer rescued VISTA<jats:sup>-\/-<\/jats:sup>survival to wild-type levels. Taken together, we propose a protective T<jats:sub>reg<\/jats:sub>-mediated role for VISTA by which inflammation-induced tissue injury is suppressed and improves survival in early-stage murine sepsis. Thus, enhancing VISTA expression or adoptively transferring VISTA<jats:sup>+<\/jats:sup>T<jats:sub>regs<\/jats:sub>in early-stage sepsis may provide a novel therapeutic approach to ameliorate inflammation-induced death.<\/jats:p>","DOI":"10.3389\/fimmu.2022.861670","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T06:32:54Z","timestamp":1648535574000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Negative Immune Checkpoint Protein, VISTA, Regulates the CD4+ Treg Population During Sepsis Progression to Promote Acute Sepsis Recovery and Survival"],"prefix":"10.3389","volume":"13","author":[{"given":"Chyna C.","family":"Gray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Biron-Girard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle 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