VISTA, a novel regulator of immunity and autoimmunity

描述（由申请人提供）：我们已经发现，表征和功能定义了一种新的，造血受限的，结构独特的，ig超家族抑制配体，其细胞外结构域与B7家族配体PD- L1同源，并对免疫产生深远影响。它被命名为v区含免疫球蛋白T细胞活化抑制因子（VISTA）。VISTA仅在造血室内发生，在骨髓抗原呈递细胞上最显著，在CD4+ T细胞和Foxp3+调节性T细胞（Treg）的一个亚群上强度较低。一种可溶性的VISTA- ig融合蛋白，或天然的VISTA，深刻地抑制体外T活性并诱导Foxp3的表达。阻断性抗vista单抗可干扰vista诱导的实验性变应性脑脊髓炎（EAE）的抑制和加剧。VISTA-/-小鼠有自发性炎性疾病的早期迹象。与所有其他pd配体相关分子不同，VISTA的造血限制以及其深刻的抑制活性和独特的结构特征表明，VISTA是一种新的、功能上不冗余的、中枢的、负性的免疫调节剂。本建议的具体目标是：1。确定VISTA如何抑制致病性脑源性T细胞的发育。VISTA控制致病性髓磷脂反应性CD4+ T细胞发育的机制将在使用VISTA、VISTA-/-或有条件表达VISTA aflox /flox的小鼠中确定。这些方法将描述VISTA在EAE中表达于CD4+ T细胞、Treg细胞、dc细胞和骨髓细胞上的功能。2. 对VISTA进行结构研究，确定VISTA功能的分子决定因素，并协助生产用于治疗的具有生物活性的VISTA- ig蛋白。结构研究将确定VISTA功能基础的化学和物理决定因素和组织特性。一个独特的主序列特征预示着VISTA具有独特的特征，包括一种新的g-褶皱变异和一种意想不到的自结合模式。3)绘制VISTA诱导的信号级联图，鉴定VISTA受体(R)。我们已经生产了多聚体VISTA分子，以识别VISTA R承载细胞。通过表达克隆对VISTA R进行鉴定。此外，将描述VISTA R触发的早期信号级联。4. 靶向VISTA途径对自身免疫的免疫干预。这一特定目的的目的是确定通过VISTA途径的夸大信号是否会抑制免疫并对自身免疫性疾病发挥治疗作用。

DESCRIPTION (provided by applicant): We have discovered, characterized and functionally defined a novel, hematopoietically-restricted, structurally- distinct, Ig-superfamily inhibitory ligand whose extracellular domain bears homology to the B7 family ligand PD- L1 and profoundly impacts on immunity. It is named V-region Immunoglobulin-containing Suppressor of T cell Activation (VISTA). VISTA is exclusively within the hematopoietic compartment, most prominently on myeloid antigen-presenting cells, with lower intensity on CD4+ T cells and a subset of Foxp3+ regulatory T cells (Treg). A soluble VISTA-Ig fusion protein, or natural VISTA profoundly inhibits in vitro T activities and induces Foxp3 expression. A blocking anti-VISTA mab interfered with VISTA-induced suppression and intensified experimental allergic encephalomyelitis (EAE). VISTA-/- mice have early indications of spontaneous inflammatory disease. Unlike all other PD-Ligand-related molecules, the hematopoietic restriction of VISTA together with its profound suppressive activities and unique structural features, illustrates that VISTA is a novel, functionally non-redundant, central, negative regulator of immunity. The Specific Aims of this proposal are: 1. Determine how VISTA suppresses the development of pathogenic encephalitogenic T cells. The mechanisms through which VISTA controls the development of pathogenic, myelin-reactive CD4+ T cells will be determined in mice treated with ¿VISTA, in VISTA-/- or in mice that conditionally express VISTAflox/flox. Such approaches will delineate the function of VISTA expressed on CD4+ T cells, Treg, DCs and myeloid cells in EAE. 2. To perform structural studies on VISTA and define the molecular determinants of VISTA function and assist in producing biologically active VISTA-Ig proteins for therapy. Structural studies will identify the chemical and physical determinants and organizational properties that underlie VISTA function. A distinctive primary sequence signature predicts that VISTA possesses unique features, including a novel variation of the Ig-fold and an unexpected mode of self-association. 3) To map the signaling cascades induced by VISTA and identify the VISTA Receptor (R). We have produced multimeric VISTA molecules that identify VISTA R bearing cells. Through expression cloning the VISTA R will be identified. In addition, the early signaling cascades of VISTA R triggering will be delineated. 4. Target the VISTA pathway for immune intervention in autoimmunity. The purpose of this specific aim is to determine if exaggerated signaling via the VISTA pathway will suppress immunity and exert a therapeutic benefit on autoimmune disease. PUBLIC HEALTH RELEVANCE: Checkpoint regulators represent a class of molecules that exert profound impact on the development of immunity. We have defined a new checkpoint regulator whose activity has been shown to impact on the development of immunity, autoimmunity and cancer. Already, fully humanahuman monoclonal antibodies are being produced for planned clinical trials. The basic immunology presented in this application is critica for sound therapeutic development of VISTA and VISTA agonists. This new molecule will be an important new target in the treatment of a wide range of immune-related diseases.