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VISTA is an acidic pH-selective ligand for PSGL-1

机译：VISTA是PSGL-1的酸性pH选择性配体

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摘要

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer(1,2). Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies(3). However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.
机译：共抑制性免疫受体可导致癌症患者的T细胞功能障碍（1,2）。阻断针对细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和程序性细胞死亡1（PD-1）的抗体可以部分逆转这种作用，并且在越来越多的恶性肿瘤中成为治疗的标准（3）。然而，尚未完全理解使肿瘤变得不适用于T细胞的许多其他轴。在这里我们报告说，T细胞活化的V域免疫球蛋白抑制剂（VISTA）在酸性pH下（例如在肿瘤微环境中发现）选择性地参与和抑制T细胞。沿VISTA细胞外域边缘的多个组氨酸残基介导与粘附和共抑制受体P-选择蛋白糖蛋白配体1（PSGL-1）的结合。经过改造以在酸性环境中选择性结合并阻断这种相互作用的抗体足以逆转VISTA介导的体内免疫抑制作用。这些发现确定了VISTA可能引起对抗肿瘤免疫反应的抗性机制，以及pH在免疫共受体参与中的出乎意料的决定性作用。

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