S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission.
Linlu TianYongxia WuHee-Jin ChoiXiaohui SuiXinlei LiM Hanief SofiMohamed Faisal KassirXiao ChenShikhar MehrotraBesim OgretmenXue-Zhong YuPublished in: Cellular & molecular immunology (2022)
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.
Keyphrases
- stem cell transplantation
- bone marrow
- hematopoietic stem cell
- allogeneic hematopoietic stem cell transplantation
- oxidative stress
- signaling pathway
- acute myeloid leukemia
- induced apoptosis
- primary care
- liver failure
- gene expression
- low dose
- transcription factor
- dna methylation
- case report
- genome wide
- cell death
- extracorporeal membrane oxygenation
- cell cycle arrest
- tyrosine kinase
- hepatitis b virus