Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

References

  1. Voermans C, Hazenberg MD. Cellular therapies for graft-versus-host disease: a tale of tissue repair and tolerance. Blood. 2020;136:410–7.

    Article  PubMed  Google Scholar 

  2. Zeiser R, Blazar BR. Acute graft-versus-host disease–biologic process, prevention, and therapy. N. Engl J Med. 2017;377:2167–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, et al. One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2:e91–100.

    Article  PubMed  Google Scholar 

  4. Ghimire S, Weber D, Mavin E, Wang XN, Dickinson AM, Holler E. Pathophysiology of GvHD and other HSCT-related major complications. Front Immunol. 2017;8:79.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Spiegel S, Milstien S. The outs and the ins of Sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11:403–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Spiegel S, Milstien S. Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem. 2007;282:2125–9.

    Article  PubMed  CAS  Google Scholar 

  7. Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, et al. Regulation of histone acetylation in the nucleus by Sphingosine-1-Phosphate. Science. 2009;325:1254–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Kwong EK, Li X, Hylemon PB, Zhou H. Sphingosine Kinases/Sphingosine 1-Phosphate signaling in hepatic lipid metabolism. Curr Pharm Rep. 2017;3:176–83.

    Article  CAS  Google Scholar 

  9. Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 2018;18:33–50.

    Article  PubMed  CAS  Google Scholar 

  10. Chi H. Sphingosine-1-Phosphate and immune regulation: trafficking and beyond. Trends Pharmacol Sci. 2011;32:16–24.

    Article  PubMed  CAS  Google Scholar 

  11. Cartier A, Hla T. Sphingosine 1-Phosphate: Lipid signaling in pathology and therapy. Science 2019;366:eaar5551.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Proia RL, Hla T. Emerging biology of Sphingosine-1-Phosphate: its role in pathogenesis and therapy. J Clin Invest. 2015;125:1379–87.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte Egress from Thymus and peripheral lymphoid organs is dependent on S1p Receptor 1. Nature. 2004;427:355–60.

    Article  PubMed  CAS  Google Scholar 

  14. Allende ML, Dreier JL, Mandala S, Proia RL. Expression of the Sphingosine 1-Phosphate receptor, S1p1, on T-cells controls thymic emigration. J Biol Chem. 2004;279:15396–401.

    Article  PubMed  CAS  Google Scholar 

  15. Xiong Y, et al. Cd4 T Cell Sphingosine 1-Phosphate Receptor (S1pr)1 and S1pr4 and Endothelial S1pr2 regulate afferent lymphatic migration. Sci Immunol. 2019;4:eaav1263.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Liu G, Yang K, Burns S, Shrestha S, Chi H. The S1p(1)-Mtor Axis directs the reciprocal differentiation of T(H)1 and T(Reg) cells. Nat Immunol. 2010;11:1047–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Garris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, et al. Defective Sphingosine 1-Phosphate Receptor 1 (S1p1) Phosphorylation Exacerbates Th17-mediated autoimmune neuroinflammation. Nat Immunol. 2013;14:1166–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Green JA, Cyster JG. S1pr2 links germinal center confinement and growth regulation. Immunol Rev. 2012;247:36–51.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ, Pereira JP, et al. T-Bet-dependent S1p5 Expression in Nk cells promotes egress from lymph nodes and bone marrow. J Exp Med. 2009;206:2469–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Mendoza A, Fang V, Chen C, Serasinghe M, Verma A, Muller J, et al. Lymphatic Endothelial S1p promotes mitochondrial function and survival in naive T cells. Nature. 2017;546:158–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Campello S, Lacalle RA, Bettella M, Manes S, Scorrano L, Viola A. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J Exp Med. 2006;203:2879–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Campello S, Scorrano L. Mitochondrial shape changes: orchestrating cell pathophysiology. EMBO Rep. 2010;11:678–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Morlino G, Barreiro O, Baixauli F, Robles-Valero J, Gonzalez-Granado JM, Villa-Bellosta R, et al. Miro-1 links mitochondria and microtubule dynein motors to control lymphocyte migration and polarity. Mol Cell Biol. 2014;34:1412–26.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Otera H, Ishihara N, Mihara K. New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta. 2013;1833:1256–68.

    Article  PubMed  CAS  Google Scholar 

  25. Baixauli F, Martín-Cófreces NB, Morlino G, Carrasco YR, Calabia-Linares C, Veiga E, et al. The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse. EMBO J. 2011;30:1238–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Simula L, Pacella I, Colamatteo A, Procaccini C, Cancila V, Bordi M, et al. Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and Cmyc-dependent metabolic reprogramming. Cell Rep. 2018;25:3059–73.e3010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Liao Y, Hung MC. Physiological regulation of Akt activity and stability. Am J Transl Res. 2010;2:19–42.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Chadha R, Meador-Woodruff JH. Downregulated Akt-Mtor signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia. Neuropsychopharmacology. 2020;45:1059–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Morita M, Prudent J, Basu K, Goyon V, Katsumura S, Hulea L, et al. mTOR controls mitochondrial dynamics and cell survival via Mtfp1. Mol Cell. 2017;67:922–35.e925.

    Article  PubMed  CAS  Google Scholar 

  30. Ma EH, Poffenberger MC, Wong AH, Jones RG. The role of Ampk in T cell metabolism and function. Curr Opin Immunol. 2017;46:45–52.

    Article  PubMed  CAS  Google Scholar 

  31. Tamas P, Hawley SA, Clarke RG, Mustard KJ, Green K, Hardie DG, et al. Regulation of the energy sensor Amp-activated protein kinase by antigen receptor and Ca2+ in T Lymphocytes. J Exp Med. 2006;203:1665–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Xing SS, Yang XY, Zheng T, Li WJ, Wu D, Chi JY, et al. Salidroside improves endothelial function and alleviates atherosclerosis by activating a mitochondria-related Ampk/Pi3k/Akt/Enos pathway. Vasc Pharmacol. 2015;72:141–52.

    Article  CAS  Google Scholar 

  33. Wang Q, Wu S, Zhu H, Ding Y, Dai X, Ouyang C, et al. Deletion of Prkaa triggers mitochondrial fission by inhibiting the autophagy-dependent degradation of Dnm1l. Autophagy. 2017;13:404–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. MacIver NJ, Blagih J, Saucillo DC, Tonelli L, Griss T, Rathmell JC, et al. The Liver Kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol. 2011;187:4187–98.

    Article  PubMed  CAS  Google Scholar 

  35. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vazquez G, Yurchenko E, et al. The energy sensor Ampk regulates Tcell metabolic adaptation and effector responses in vivo. Immunity. 2015;42:41–54.

    Article  PubMed  CAS  Google Scholar 

  36. Nguyen H, Alawieh A, Bastian D, Kuril S, Dai M, Daenthanasanmak A, et al. Targeting the complement alternative pathway permits graft versus leukemia activity while preventing graft versus host disease. Clin Cancer Res. 2020;26:3481–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Heinrichs J, Li J, Nguyen H, Wu Y, Bastian D, Daethanasanmak A, et al. Cd8(+) Tregs promote Gvhd prevention and overcome the impaired Gvl effect mediated by Cd4(+) Tregs in mice. Oncoimmunology. 2016;5:e1146842.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sofi, MH, et al. Ceramide synthesis regulates T cell activity and Gvhd development. JCI Insight 2017;2:e91701.

    Article  PubMed Central  Google Scholar 

  39. Bielawski J, Pierce JS, Snider J, Rembiesa B, Szulc ZM, Bielawska A. Sphingolipid analysis by High Performance Liquid Chromatography-Tandem Mass Spectrometry (Hplc-Ms/Ms). Adv Exp Med Biol. 2010;688:46–59.

    Article  PubMed  CAS  Google Scholar 

  40. Dany M, Gencer S, Nganga R, Thomas RJ, Oleinik N, Baron KD, et al. Targeting Flt3-Itd signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in Aml. Blood. 2016;128:1944–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Daenthanasanmak A, Iamsawat S, Chakraborty P, Nguyen HD, Bastian D, Liu C, et al. Targeting Sirt-1 controls GVHD by inhibiting T-Cell Allo-response and promoting treg stability in mice. Blood. 2019;133:266–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Betts BC, Bastian D, Iamsawat S, Nguyen H, Heinrichs JL, Wu Y, et al. Targeting Jak2 reduces GVHD and Xenograft rejection through regulation of T cell differentiation. Proc Natl Acad Sci USA. 2018;115:1582–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wu Y, Schutt S, Paz K, Zhang M, Flynn RP, Bastian D, et al. Microrna-17-92 is required for T-Cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood. 2018;131:1974–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Sofi MH, et al. A single strain of bacteroides fragilis protects gut integrity and reduces GVHD. JCI Insight 2021;6:e136841.

    Article  PubMed Central  Google Scholar 

  45. Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 2007;8:1295–301.

    Article  PubMed  CAS  Google Scholar 

  46. Baeyens A, Fang V, Chen C, Schwab SR. Exit strategies: S1p signaling and T cell migration. Trends Immunol. 2015;36:778–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chakraborty P, Vaena SG, Thyagarajan K, Chatterjee S, Al-Khami A, Selvam SP, et al. Pro-survival lipid Sphingosine-1-Phosphate metabolically programs T cells to limit anti-tumor activity. Cell Rep. 2019;28:1879–93.e1877.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95:2754–9.

    Article  PubMed  CAS  Google Scholar 

  49. Socié G, Blazar BR. Acute graft-versus-host disease: from the bench to the bedside. Blood. 2009;114:4327–36.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Yi T, Chen Y, Wang L, Du G, Huang D, Zhao D, et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood. 2009;114:3101–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski WR. Absence of regulatory T-cell control of Th1 and Th17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007;110:3804–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. science. 1999;285:412–5.

    CAS  Google Scholar 

  53. Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I, Jain D, et al. Donor APCs are required for maximal GVHD but not for Gvl. Nat Med 2004;10:987–92.

    Article  PubMed  CAS  Google Scholar 

  54. MacDonald KPA, Kuns RD, Rowe V, Morris ES, Banovic T, Bofinger H, et al. Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD. Blood. 2007;109:5049–57.

    Article  PubMed  CAS  Google Scholar 

  55. Smith P, O’Sullivan C, Gergely P. Sphingosine 1-phosphate signaling and its pharmacological modulation in allogeneic hematopoietic stem cell transplantation. Int. J. Mol. Sci. 2017;18:2027.

    Article  PubMed Central  Google Scholar 

  56. Dutt S, Ermann J, Tseng D, Liu YP, George TI, Fathman CG, et al. L-Selectin and Beta7 Integrin on Donor Cd4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease. Blood. 2005;106:4009–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Waldman E, Lu SX, Hubbard VM, Kochman AA, Eng JM, Terwey TH, et al. Absence of Beta7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine. Blood. 2006;107:1703–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Duffner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P, et al. Role of Cxcr3-induced donor T-cell migration in Acute GVHD. Exp Hematol 2003;31:897–902.

    Article  PubMed  CAS  Google Scholar 

  59. Varona R, Cadenas V, Gómez L, Martínez AC, Márquez G. Ccr6 regulates Cd4+ T-cell-mediated acute graft-versus-host disease Responses. Blood. 2005;106:18–26.

    Article  PubMed  CAS  Google Scholar 

  60. Xin Q, Cheng G, Kong F, Ji Q, Li H, Jiang W, et al. Stat1 transcriptionally regulates the expression of S1pr1 by binding its promoter region. Gene. 2020;736:144417.

    Article  PubMed  CAS  Google Scholar 

  61. Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada A, Huang WC, et al. Sphingosine-1-Phosphate links persistent Stat3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013;23:107–20.

    Article  PubMed  CAS  Google Scholar 

  62. Schnute ME, McReynolds MD, Kasten T, Yates M, Jerome G, Rains JW, et al. Modulation of cellular S1p levels with a novel, potent and specific inhibitor of Sphingosine Kinase-1. Biochem J. 2012;444:79–88.

    Article  PubMed  CAS  Google Scholar 

  63. Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1p1 antagonist in vivo. Nat Chem Biol 2006;2:434–41.

    Article  PubMed  CAS  Google Scholar 

  64. Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, et al. Sphingosine 1-Phosphate (S1p) Receptor subtypes S1p1 and S1p3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004;279:13839–13848.

    Article  PubMed  CAS  Google Scholar 

  65. Baeyens A, Bracero S, Chaluvadi VS, Khodadadi-Jamayran A, Cammer M, Schwab SR. Monocyte-derived S1p in the lymph node regulates immune responses. Nature. 2021;592:290–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Dan HC, Ebbs A, Pasparakis M, Van Dyke T, Basseres DS, Baldwin AS. Akt-dependent activation of Mtorc1 complex involves phosphorylation of mTOR (Mammalian Target of Rapamycin) by Iκb Kinase Α (Ikkα). J Biol Chem. 2014;289:25227–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Jones N, Cronin JG, Dolton G, Panetti S, Schauenburg AJ, Galloway S, et al. Metabolic adaptation of human Cd4(+) and Cd8(+) T-cells to T-cell receptor-mediated stimulation. Front Immunol. 2017;8:1516.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Nguyen HD, Chatterjee S, Haarberg KMK, Wu Y, Bastian D, Heinrichs J, et al. Metabolic reprogramming of alloantigen-activated T Cells after hematopoietic cell transplantation. J Clin Invest. 2016;126:1337–52.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Lee CF, Lo YC, Cheng CH, Furtmuller GJ, Oh B, Andrade-Oliveira V, et al. Preventing allograft rejection by targeting immune metabolism. Cell Rep. 2015;13:760–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Desdín-Micó G, Soto-Heredero G, Mittelbrunn M. Mitochondrial activity in T cells. Mitochondrion. 2018;41:51–7.

    Article  PubMed  Google Scholar 

  71. Li YH, Xu F, Thome R, Guo MF, Sun ML, Song GB, et al. Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis. J Neuroinflammation. 2019;16:149.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Losón OC, Hellberg K, et al. Metabolism. Amp-activated protein kinase mediates mitochondrial fission in response to energy stress. Science. 2016;351:275–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4:397–407.

    Article  PubMed  CAS  Google Scholar 

  74. Allende ML, Sasaki T, Kawai H, Olivera A, Mi Y, van Echten-Deckert G, et al. Mice deficient in Sphingosine Kinase 1 are rendered lymphopenic by Fty720. J Biol Chem. 2004;279:52487–92.

    Article  PubMed  CAS  Google Scholar 

  75. Kharel Y, Raje M, Gao M, Gellett AM, Tomsig JL, Lynch KR, et al. Sphingosine Kinase Type 2 inhibition elevates circulating sphingosine 1-Phosphate. Biochem J. 2012;447:149–57.

    Article  PubMed  CAS  Google Scholar 

  76. Tsai HC, Han MH. Sphingosine-1-Phosphate (S1p) and S1p signaling pathway: therapeutic targets in autoimmunity and inflammation. Drugs. 2016;76:1067–79.

    Article  PubMed  Google Scholar 

  77. Taylor PA, Ehrhardt MJ, Lees CJ, Tolar J, Weigel BJ, Panoskaltsis-Mortari A, et al. Insights into the mechanism of Fty720 and compatibility with regulatory T cells for the inhibition of Graft-Versus-Host Disease (GVHD). Blood. 2007;110:3480–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, et al. Fty720 impairs Cd8 T-cell function independently of the Sphingosine-1-Phosphate pathway. J Neuroimmunol. 2014;270:13–21.

    Article  PubMed  CAS  Google Scholar 

  79. Ryu J, Jhun J, Park MJ, Baek JA, Kim SY, Cho KH, et al. Fty720 ameliorates GVHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition. J Transl Med. 2020;18:225.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Aarthi JJ, Darendeliler MA, Pushparaj PN. Dissecting the role of the S1p/S1pr axis in health and disease. J Dent Res. 2011;90:841–54.

    Article  PubMed  CAS  Google Scholar 

  81. Bielawski J, Szulc ZM, Hannun YA, Bielawska A. Simultaneous quantitative analysis of bioactive sphingolipids by high-performance Liquid Chromatography-Tandem Mass Spectrometry. Methods. 2006;39:82–91.

    Article  PubMed  CAS  Google Scholar 

  82. Sofi MH, Tian L, Schutt S, Khan I, Choi HJ, Wu Y, et al. Ceramide Synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-Ras/Erk Pathway. Leukemia. 2022;36:1907–15.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the technical support provided by the Department of Laboratory Animal Research, Flow Cytometry Core and Imaging Core as part of the Hollings Cancer Center at the MUSC, which is funded by Cancer Center Support Grant P30 CA138313 from the National Institutes of Health, National Cancer Institute (NCI).

Funding

This work is supported in part by SmartState Cancer Stem Cell Biology & Therapy Program and by R01 grants from the National Institutes of Health, including AI118305, HL140953 and CA258440 (X.-Z.Y.).

Author information

Authors and Affiliations

Authors

Contributions

LT participated in the research design and execution of the experiments, analyzed and interpreted the data, and wrote the manuscript; YW performed long-term and short-term allo-BMT experiments (WT, Sphk1−/− and Sphk2−/− transplantation from C57BL/6 mice to BALB/c mice); HC, XS, XL and HS participated in some of the experiments; MK performed the T-cell transfection assay; BO, SK, and XC participated in the research design, provided essential reagents, and/or edited and revised the manuscript; and X-ZY designed the research, interpreted the data, and edited and revised the manuscript.

Corresponding author

Correspondence to Xue-Zhong Yu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tian, L., Wu, Y., Choi, HJ. et al. S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission. Cell Mol Immunol 19, 1235–1250 (2022). https://doi.org/10.1038/s41423-022-00921-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-022-00921-x

Keywords

  • Sphk1
  • S1P
  • S1PR
  • GVHD
  • GVL
  • mitochondrial fission

Search

Quick links