Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity

V domain-containing Ig suppressor of T-cell activation (VISTA) is a negative checkpoint regulator that suppresses T cell-mediated immune responses. Previous studies using a VISTA-neutralizing monoclonal antibody show that VISTA blockade enhances T-cell activation. The current study describes a compr...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 41; p. 14846
Main Authors: Wang, Li, Le Mercier, Isabelle, Putra, Juan, Chen, Wenna, Liu, Jun, Schenk, Austin D, Nowak, Elizabeth C, Suriawinata, Arief A, Li, Jiannan, Noelle, Randolph J
Format: Journal Article
Language:English
Published: United States 14.10.2014
Subjects:
Aging - pathology
Animals
Autoimmune Diseases - genetics
Autoimmune Diseases - immunology
Autoimmunity - genetics
Autoimmunity - immunology
B7 Antigens - deficiency
B7 Antigens - genetics
B7 Antigens - metabolism
Chemokines - metabolism
Encephalomyelitis, Autoimmune, Experimental - immunology
Encephalomyelitis, Autoimmune, Experimental - pathology
Genetic Predisposition to Disease
Hematopoiesis
Inflammation - pathology
Lymphocyte Activation - immunology
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Th1 Cells - immunology
Th17 Cells - immunology
peripheral tolerance
autoimmunity
immune suppression
inflammation
ISSN:1091-6490, 1091-6490
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Summary:V domain-containing Ig suppressor of T-cell activation (VISTA) is a negative checkpoint regulator that suppresses T cell-mediated immune responses. Previous studies using a VISTA-neutralizing monoclonal antibody show that VISTA blockade enhances T-cell activation. The current study describes a comprehensive characterization of mice in which the gene for VISTA has been deleted. Despite the apparent normal hematopoietic development in young mice, VISTA genetic deficiency leads to a gradual accumulation of spontaneously activated T cells, accompanied by the production of a spectrum of inflammatory cytokines and chemokines. Enhanced T-cell responsiveness was also observed upon immunization with neoantigen. Despite the presence of multiorgan chronic inflammation, aged VISTA-deficient mice did not develop systemic or organ-specific autoimmune disease. Interbreeding of the VISTA-deficient mice with 2D2 T-cell receptor transgenic mice, which are predisposed to the development of experimental autoimmune encephalomyelitis, drastically enhanced disease incidence and intensity. Disease development is correlated with the increase in the activation of encephalitogenic T cells in the periphery and enhanced infiltration into the CNS. Taken together, our data suggest that VISTA is a negative checkpoint regulator whose loss of function lowers the threshold for T-cell activation, allowing for an enhanced proinflammatory phenotype and an increase in the frequency and intensity of autoimmunity under susceptible conditions.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1407447111