VISTA, a novel regulator of immunity and autoimmunity

描述（由申请人提供）：我们发现、表征和功能上定义了一种新的、造血限制性的、结构上不同的Ig超家族抑制性配体，其胞外结构域与B7家族配体PD-L1具有同源性并对免疫力产生深远影响。它被命名为V区免疫球蛋白含有抑制T细胞活化（VISTA）。VISTA仅在造血区室内，最显著地在髓样抗原呈递细胞上，在CD 4 + T细胞和Foxp 3+调节性T细胞（Treg）的子集上具有较低的强度。可溶性VISTA-Ig融合蛋白或天然VISTA深刻地抑制体外T活性并诱导Foxp 3表达。阻断性抗VISTA单抗干扰VISTA诱导的抑制并加剧实验性过敏性脑脊髓炎（EAE）。VISTA-/-小鼠具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说明VISTA是一种新型的、功能上非冗余的、中枢性的免疫负调节剂。该提案的具体目标是：1。确定VISTA如何抑制致病性致脑炎性T细胞的发展。VISTA控制致病性髓鞘反应性CD 4 + T细胞发展的机制将在用VISTA处理的小鼠、VISTA-/-或条件性表达VISTAflox/flox的小鼠中确定。此类方法将描绘EAE中在CD 4 + T细胞、Treg、DC和骨髓细胞上表达的VISTA的功能。2.对VISTA进行结构研究，确定VISTA功能的分子决定因素，并协助生产具有生物活性的VISTA-Ig蛋白用于治疗。结构研究将确定化学和物理的决定因素和组织属性，VISTA功能的基础。独特的一级序列特征预测VISTA具有独特的特征，包括Ig折叠的新变化和意想不到的自缔合模式。3)绘制VISTA诱导的信号级联并鉴定VISTA受体（R）。我们已经产生了鉴定携带VISTA R的细胞的多聚体VISTA分子。通过表达克隆，将鉴定VISTA R。此外，将描绘VISTA R触发的早期信号级联。4.靶向VISTA通路，用于自身免疫的免疫干预。该特定目标的目的是确定经由VISTA途径的过度信号传导是否将抑制免疫并对自身免疫性疾病发挥治疗益处。 公共卫生相关性：检查点调节剂代表一类对免疫力发展产生深远影响的分子。我们已经定义了一种新的检查点调节剂，其活性已被证明会影响免疫，自身免疫和癌症的发展。完全人源化的单克隆抗体已经被生产出来用于计划中的临床试验。本申请中提出的基础免疫学对于VISTA和VISTA激动剂的合理治疗开发至关重要。这种新分子将成为治疗多种免疫相关疾病的重要新靶点。

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.