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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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS Jg. 111; H. 41; S. 14846
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 14.10.2014
Schlagworte:	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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Abstract	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.
AbstractList	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.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. 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.
Author	Le Mercier, Isabelle Putra, Juan Wang, Li Noelle, Randolph J Chen, Wenna Nowak, Elizabeth C Schenk, Austin D Liu, Jun Suriawinata, Arief A Li, Jiannan
Author_xml	– sequence: 1 givenname: Li surname: Wang fullname: Wang, Li email: lilywang@mcw.edu, randolph.j.noelle@dartmouth.edu organization: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; lilywang@mcw.edu randolph.j.noelle@dartmouth.edu – sequence: 2 givenname: Isabelle surname: Le Mercier fullname: Le Mercier, Isabelle organization: Departments of Microbiology and Immunology – sequence: 3 givenname: Juan surname: Putra fullname: Putra, Juan organization: Pathology, and – sequence: 4 givenname: Wenna surname: Chen fullname: Chen, Wenna organization: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226 – sequence: 5 givenname: Jun surname: Liu fullname: Liu, Jun organization: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226 – sequence: 6 givenname: Austin D surname: Schenk fullname: Schenk, Austin D organization: Surgery, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756 – sequence: 7 givenname: Elizabeth C surname: Nowak fullname: Nowak, Elizabeth C organization: Departments of Microbiology and Immunology – sequence: 8 givenname: Arief A surname: Suriawinata fullname: Suriawinata, Arief A organization: Pathology, and – sequence: 9 givenname: Jiannan surname: Li fullname: Li, Jiannan organization: Departments of Microbiology and Immunology – sequence: 10 givenname: Randolph J surname: Noelle fullname: Noelle, Randolph J email: lilywang@mcw.edu, randolph.j.noelle@dartmouth.edu organization: Departments of Microbiology and Immunology, Medical Research Council Centre of Transplantation, Guy's Hospital, King's College London, King's Health Partners, London SE1 9RT, United Kingdom lilywang@mcw.edu randolph.j.noelle@dartmouth.edu
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SubjectTerms	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
Title	Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity
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