{"doi":"10.3389/fimmu.2022.861670","title":"Negative Immune Checkpoint Protein, VISTA, Regulates the CD4+ Treg Population During Sepsis Progression to Promote Acute Sepsis Recovery and Survival","abstract":"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 V -domain I mmunoglobulin S uppressor of T cell A ctivation (VISTA) is an ideal candidate for strategic targeting in sepsis. We hypothesized that immune checkpoint regulator, VISTA, controls T-regulatory cells (T reg ), 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 reg -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 + T regs in VISTA-gene deficient (VISTA -/- ) and wild-type mice. We also measured changes in survival, soluble indices of tissue injury, and circulating cytokines in the VISTA -/- and wild-type mice. We found that in wild-type mice, CD4 + T regs exhibit a significant upregulation of VISTA which correlates with higher T reg abundance in the spleen and small intestine following septic insult. However, VISTA -/- mice have reduced T reg abundance in these compartments met with a higher expression of Foxp3, CTLA4, and CD25 compared to wild-type mice. VISTA -/- 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, TNFα, IL-17F, IL-23, and MCP-1) following septic challenge. To elucidate the role of T regs in VISTA -/- sepsis mortality, we adoptively transferred VISTA-expressing T regs into VISTA -/- mice. This adoptive transfer rescued VISTA -/- survival to wild-type levels. Taken together, we propose a protective T reg -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 + T regs in early-stage sepsis may provide a novel therapeutic approach to ameliorate inflammation-induced death.","journal":"Frontiers in Immunology","year":2022,"id":250388,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":892548,"name":"Bethany Biron-Girard","orcid":null,"position":1,"is_corresponding":false},{"id":892054,"name":"Michelle E. Wakeley","orcid":"0000-0001-7850-5744","position":2,"is_corresponding":false},{"id":506693,"name":"Chun‐Shiang Chung","orcid":"0000-0003-4089-6182","position":3,"is_corresponding":false},{"id":736442,"name":"Yaping Chen","orcid":"0000-0001-6748-7448","position":4,"is_corresponding":false},{"id":892549,"name":"Yael Quiles-Ramirez","orcid":null,"position":5,"is_corresponding":false},{"id":892550,"name":"Jessica D. Tolbert","orcid":null,"position":6,"is_corresponding":false},{"id":506696,"name":"Alfred Ayala","orcid":"0000-0002-5034-2995","position":7,"is_corresponding":false},{"id":878012,"name":"Chyna C. Gray","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:24:28.242323Z","pmid":"35401514","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}