Immunology T lymphocytes are central mediators of adaptive immunity, playing a key role in both appropriate immune responses (such as immunity against pathogens) and abnormal ones (such as autoimmune response that lead to type 1 diabetes). Optimal activation, proliferation, and differentiation to effector function of T cells require a simultaneous occurrence of two signals: antigen specific signals via T cell antigen receptors, and additional costimulatory signals (costimulation) generated mainly by the interaction between the B7 and CD28 families. The intense effort towards understanding T cell costimulation of B7-1, B7-2/CD28, CTLA-4 pathway over the past decade has shaped much of our understanding regarding the immune system and immune-related diseases such as type 1 diabetes. We have discovered the newest member of the B7 family, B7x, which is capable of inhibiting T cell function in vitro (coinhibition). However, the role of B7x in diabetes is unknown. Interestingly, we have recently found that, unlike B7-1 and B7-2, both human and mouse B7x genes are located in insulin- dependent diabetes loci and are expressed in pancreatic islets. Moreover, we have found that transgenic mice overexpressing B7x in pancreatic ? cells are resistant to CD4 T cell mediated type 1 diabetes. Based on the preliminary data, we have hypothesized that B7x represents a novel T cell coinhibitory pathway that attenuates effector T cell function in pancreas. We have generated a number of important tools (mAbs to B7x, B7x transgenic mice, B7x knock-out mice, etc.) that provide us with unique opportunities to analyze the role of B7x pathway in type 1 diabetes. Overall, the studies of this project may not only advance our understanding of the pathogenic processes underlying type 1 diabetes and its complicatios but also lead to a rational approach for clinical therapeutic intervention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZDK1-GRB-B (O1))
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Spain, Lisa M
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Albert Einstein College of Medicine
Schools of Medicine
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Cheng, Haiying; Borczuk, Alain; Janakiram, Murali et al. (2018) Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers. Clin Cancer Res 24:1954-1964
Scandiuzzi, Lisa; Ghosh, Kaya; Hofmeyer, Kimberly A et al. (2014) Tissue-expressed B7-H1 critically controls intestinal inflammation. Cell Rep 6:625-32
Vigdorovich, Vladimir; Ramagopal, Udupi A; Lázár-Molnár, Eszter et al. (2013) Structure and T cell inhibition properties of B7 family member, B7-H3. Structure 21:707-17
Zhao, Ruihua; Chinai, Jordan M; Buhl, Susan et al. (2013) HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc Natl Acad Sci U S A 110:9879-84
Abadi, Yael M; Jeon, Hyungjun; Ohaegbulam, Kim C et al. (2013) Host b7x promotes pulmonary metastasis of breast cancer. J Immunol 190:3806-14
Janakiram, Murali; Abadi, Yael M; Sparano, Joseph A et al. (2012) T cell coinhibition and immunotherapy in human breast cancer. Discov Med 14:229-36
Lee, Jun Sik; Scandiuzzi, Lisa; Ray, Anjana et al. (2012) B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells. J Immunol 189:4165-74
Hofmeyer, Kimberly A; Scandiuzzi, Lisa; Ghosh, Kaya et al. (2012) Tissue-expressed B7x affects the immune response to and outcome of lethal pulmonary infection. J Immunol 189:3054-63
Scandiuzzi, Lisa; Ghosh, Kaya; Zang, Xingxing (2011) T cell costimulation and coinhibition: genetics and disease. Discov Med 12:119-28
Hofmeyer, Kimberly A; Jeon, Hyungjun; Zang, Xingxing (2011) The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion. J Biomed Biotechnol 2011:451694

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