V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator of T cells. We assessed VISTA deficient mice in the murine nephrotoxic nephritis models of acute and chronic immune-complex mediated glomerulonephritis. We show that VISTA deficiency protects from crescentic glomerulonephritis, with no effect on the nephritogenic adaptive immune response. The early neutrophil influx was unaffected but proteinuria was reduced suggesting a reduction in neutrophil activation. In vivo, there was reduced neutrophil degranulation in VISTA deficienct mice and, in vitro, VISTA-deficient neutrophils had an impaired response to immune complexes but not to fMLP or PMA. Mice with a genetic deficiency of neutrophils due to myeloid-specific deletion of myeloid cell leukemia 1 (Mcl-1) were also protected from crescentic glomerulonephritis, indicating an essential role for neutrophils. Therefore, VISTA deficiency inhibits neutrophil activation by immune complexes and neutrophil-dependent crescentic glomerulonephritis. This suggests that VISTA is a therapeutic target for inflammatory disease. However, this would need to be balanced against a potential enhancing effect on autoimmunity.

含有 V 型免疫球蛋白结构域的 T 细胞激活抑制因子 (VISTA) 是 T 细胞的负检查点调节因子。我们在急性和慢性免疫复合物介导的肾小球肾炎的小鼠肾毒性肾炎模型中评估了 VISTA 缺陷小鼠。我们发现 VISTA 缺乏可以预防新月体肾小球肾炎，但对肾源性适应性免疫反应没有影响。早期中性粒细胞流入不受影响，但蛋白尿减少，表明中性粒细胞活化减少。在体内，VISTA 缺陷小鼠的中性粒细胞脱颗粒减少，在体外，VISTA 缺陷的中性粒细胞对免疫复合物的反应受损，但对 fMLP 或 PMA 的反应不受影响。由于髓系细胞白血病 1 (Mcl-1) 的髓系特异性缺失而导致中性粒细胞遗传缺陷的小鼠也能免受新月体肾小球肾炎的影响，这表明中性粒细胞的重要作用。因此，VISTA 缺乏会抑制免疫复合物对中性粒细胞的激活，并抑制中性粒细胞依赖性新月体肾小球肾炎。这表明 VISTA 是炎症性疾病的治疗靶点。然而，这需要与自身免疫的潜在增强作用相平衡。