Costimulatory genes and molecules have a profound impact on autoimmune diseases and recent data suggests that these molecules also control genetic susceptibility to many human autoimmune diseases. Of the costimulatory receptors, CD28/CTLA4 has gained considerable attention because loss of CTLA4 results in multi-organ autoimmune diseases in mouse. Multiple autoimmune diseases in man and mouse have shown linkage to CTLA4 and this has been attributed to differential expression of various isoforms of CTLA4. There are four different isoforms of CTLA4 in mice, the smallest isoform, called 1/4 CTLA4, is highly conserved and expressed all through the species but its function is not known. In addition to CD28/CTLA4, there is a parallel costimulatory pathway, CD226/TIGIT, which has been linked to a number of human autoimmune diseases, including type 1 diabetes and multiple sclerosis. Whereas CD226 initiates a positive costimulatory signal, TIGIT has inhibitory functions. In vivo blockade of CD226 not only inhibits T cell functions but also generates inhibitory antigen presenting cells. The mechanism by which the CD226/TIGIT pathway regulates T cell and APC function has not been well understood. To address these issues we have proposed the following aims: 1.Study the role of 1/4 CTLA4 in the regulation of autoimmune T cell responses and development of autoimmune disease. 1/4 CTLA4 transgenic mice, in which CTLA4 isoform has been overexpressed in T cells, develop spontaneous autoimmune disease, the mechanism for which is not known. We will analyze whether 1/4 CTLA4 regulates expression of other isoforms of CTLA4, affects T cell survival and burst size of effector T cells and affects functions of Tregs;2. Study the role of CD226 in regulating T cell responses and functions of antigen presenting cells. We will determine whether CD226 affects the expansion and function of effector T cells, Tregs or changes APC function. This will be accomplished by using a blocking anti-CD226 antibody that we have generated and CD226-deficient mice that we have obtained;3. Study the mechanism by which TIGIT mediates its Inhibitory effects. We will study whether TIGIT regulates T cells, Tregs or APC function by using TIGIT-deficient mice. In addition, we will determine whether TIGIT-deficient mice develop spontaneous autoimmunity. These studies will provide fundamental information on the mechanisms by which the negative costimulatory molecules associated with genetic susceptibility play a role in the regulation of autoimmune diseases.

Public Health Relevance

In this grant application we propose to analyze two different costimulatory pathways: CD28/CTLA4 and CD226/TIGIT, both of which have been genetically linked to human autoimmune diseases. We anticipate that modulation of these pathways by blocking reagents would be of greatest benefit to human autoimmune diseases, type 1 diabetes and multiple sclerosis.

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Yale University
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Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang et al. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337-43
Esposito, Laura; Hunter, Kara M D; Clark, Jan et al. (2014) Investigation of soluble and transmembrane CTLA-4 isoforms in serum and microvesicles. J Immunol 193:889-900
Stern, Joel N H; Yaari, Gur; Vander Heiden, Jason A et al. (2014) B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med 6:248ra107
Manzel, Arndt; Muller, Dominik N; Hafler, David A et al. (2014) Role of "Western diet" in inflammatory autoimmune diseases. Curr Allergy Asthma Rep 14:404
Sage, Peter T; Paterson, Alison M; Lovitch, Scott B et al. (2014) The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41:1026-39
Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita et al. (2014) Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. J Clin Invest 124:2513-22
Gautron, Anne-Sophie; Dominguez-Villar, Margarita; de Marcken, Marine et al. (2014) Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells. Eur J Immunol 44:2703-11
Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81
Kleinewietfeld, Markus; Hafler, David A (2014) Regulatory T cells in autoimmune neuroinflammation. Immunol Rev 259:231-44
Lee, Youjin; Collins, Mary; Kuchroo, Vijay K (2014) Unexpected targets and triggers of autoimmunity. J Clin Immunol 34 Suppl 1:S56-60

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