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.

中文翻译：

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VISTA 非冗余调节小鼠脓毒症肠道中的增殖和 CD69low γδ T 细胞积累。

脓毒症是一种对感染的系统性免疫反应失调，约 35% 的院内死亡由脓毒症造成，医疗费用高昂。我们的实验室等已经证明了靶向阴性检查点调节因子 (NCR) 可以提高脓毒症、盲肠结扎和穿刺 (CLP) 小鼠模型的存活率。B7-CD28 超家族成员，T 细胞激活的 V 结构域免疫球蛋白抑制因子 (VISTA)，是脓毒症战略靶向的理想候选者。VISTA 是一种 35-45 kDa 1 型跨膜蛋白，具有独特的生物学特性，使其有别于所有其他 NCR。我们最近报道，VISTA-/- 小鼠在 CLP 后有显着的生存缺陷，通过过继转移表达 VISTA 的 pMSCV 小鼠 Foxp3-EF1α-GFP-T2A-puro 稳定的 Jurkat 细胞系（Jurkatfoxp3 T 细胞）来挽救这种缺陷。基于我们之前的研究，我们研究了 VISTA-/- 小鼠中 Jurkatfoxp3 T 细胞的效应细胞靶点。γδ T 细胞是强大的淋巴亚群，需要 Tregs 进行调节微调以防止明显的炎症/病理。在这项研究中，我们假设 Jurkatfoxp3 T 细胞在 CLP 后非冗余地调节 γδ T 细胞群。我们发现 VISTA-/- 小鼠肠道 CD69low γδ T 细胞的积累增加，而这对小鼠败血症没有保护作用。Jurkatfoxp3 T 细胞的过继转移，减少了肠道 γδ T 细胞群，抑制了增殖，使剩余的 γδ T 细胞偏向 CD69high 表型，并在 CLP 后 VISTA-/- 小鼠中增加了 sCD40L。这些结果支持了 VISTA 改变小鼠脓毒症中肠道 γδ T 细胞谱系代表性的潜在调节机制。