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| 1 | S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission显示文摘Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders. | Linlu Tian Yongxia Wu Hee-Jin Choi Xiaohui Sui Xinlei Li M.Hanief Sofi Mohamed Faisal Kassir Xiao Chen Shikhar Mehrotra Besim Ogretmen Xue-zhong Yu | 2022 | Cellular & Molecular Immunology2022，19，11： | 2 |
| 2 | Shewanella secretes fla- vins that mediate extracellular electron transfer显示文摘 | MARSILI E BATON D B SHIKHARE I D | 2008 | Proc Natl Acad Sci2008，105，： | 1 |
| 3 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | Marsili E Baron DB Shikhare ID | 2008 | Proceedings of the National Academy of Sciences of the United States of Ameria2008，105，10： | 1 |
| 4 | Meta-Analysis of Transcatheter Closure Versus Medical Therapy for Patent Foramen Ovale in Prevention of Recurrent Neurological Events After Presumed Paradoxical Embolism显示文摘 | Shikhar Agarwal Navkaranbir Singh Bajaj Dharam J. Kumbhani E. Murat Tuzcu Samir R. Kapadia | 2012 | JACC: Cardiovascular Interventions2012，，7： | 1 |
| 5 | Is reaction time variability consistent across sensory modalities? Insights from latent variable ana- lysis of single-trial P3b latencies 显示文摘 | Saville CW Shikhare S Iyengar S | 2012 | Biol Psychol2012，91，2： | 1 |
| 6 | Inflammatory bowel disease in children: current trends显示文摘 | Gargi Shikhare Subra Kugathasan | 2010 | Journal of Gastroenterology2010，，7： | 1 |
| 7 | Shewanella se- cretes flavins that mediate extracellular electron transfer 显示文摘 | Marsili E Baron D B Shikhare I D | 2008 | Proceedings of the National Academy of Sciences2008，105，10： | 1 |
| 8 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | Marsili E Baron D B Shikhare I D | 2008 | Proc Natl Acad Sci USA2008，105，： | 1 |
| 9 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | Marsili E Baron D B Shikhare I D | 2008 | Proceedings of the National Academy of Sciences2008，105，10： | 1 |
| 10 | The Effect of Team Leader Characteristics on Learning, Knowledge Application, and Performance of Cross-Functional New Product Develop- ment Teams显示文摘 | Sarin Shikhar Mcdermott Christopher | 2003 | Decision Sciences2003，，4： | 1 |
| 11 | The effect of team leader characteristics on learning, knowledge application, and performance of cross - functional new product development teams显示文摘 | Shikhar S Christopher M | 2003 | Decision Sciences2003，34，70： | 1 |
| 12 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | Marsili E Baron D B Shikhare I D et 81 | 2008 | Proe Nail Acad Sci U S A2008，105，： | 1 |
| 13 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | Marsili E Baron DB Shikhare ID | 2008 | Pro- ceedings of the National Academy of Sciences2008，105，10： | 1 |
| 14 | Shewanella secretes flavins that mediate extracellular electron transfer 显示文摘 | Marsili E baraon DB Shikhare ID Coursolle D Gralnick JA Bond DR | 2008 | PNAS2008，105，10： | 1 |
| 15 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | Marsili E Baron D B Shikhare I D | 2008 | PNAS2008，105，： | 1 |
| 16 | The Effect of Team Leader Characteristics on Learning,Knowledge Application,and Performance of Cross-Functional New Product Development Teams 显示文摘 | SARIN SHIKHAR MCDERMOTT CHRISTOPHER | 2003 | Decision Sciences2003，34，4： | 1 |
| 17 | Shewanella secretes flavins that mediate extracellular electron transfer显示文摘 | MARSILI E BARON D B SHIKHARE I D | 2008 | Proceedings of the National Academy of Sciences2008，105，10： | 1 |
| 18 | Contour line tracing algorithm for digital topographic maps 显示文摘 | PRADHAN R SHIKHAR KUMAR L AGARWAL R PRADHAN M P GHOSE M K | 2010 | International Journal of Image Processing (IJIP)2010，4，2： | 1 |
| 19 | Inflammatory bowel disease in children: current trends 显示文摘 | Shikhare G Kugathasan S | 2010 | J Gastroenterol2010，45，7： | 1 |
| 20 | Zeus: surface modeling, surface grid generation, tetrahedral volume dis- cretization显示文摘 | Shikhare D Gopalsamy S Reddy T S | 1999 | Computers & Graphics1999，23，： | 1 |
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