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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI098007-02
Application #
8463984
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Esch, Thomas R
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$527,943
Indirect Cost
$169,888
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Lines, J Louise; Sempere, Lorenzo F; Broughton, Thomas et al. (2014) VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2:510-7
Lines, J Louise; Pantazi, Eirini; Mak, Justin et al. (2014) VISTA is an immune checkpoint molecule for human T cells. Cancer Res 74:1924-32
Le Mercier, Isabelle; Chen, Wenna; Lines, Janet L et al. (2014) VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res 74:1933-44
Ceeraz, Sabrina; Nowak, Elizabeth C; Noelle, Randolph J (2013) B7 family checkpoint regulators in immune regulation and disease. Trends Immunol 34:556-63