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

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Cellular & Molecular Immunology 2022年第11期19卷 1235-1250页

作者： 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 Department of Microbiology&Immunology Medical University of South CarolinaCharlestonSCUSA Department of Microbiology&Immunology Medical College of WisconsinMilwaukeeWIUSA Department of Medicine Medical College of WisconsinMilwaukeeWIUSA Department of Biochemistry&Molecular Biology Medical University of South CarolinaCharlestonSCUSA Department of Surgery Medical University of South CarolinaCharlestonSCUSA Hollings Cancer Center Medical University of South CarolinaCharlestonSCUSA the Cancer Center Medical College of WisconsinMilwaukeeWIUSA

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.

关键词： Sphk1 S1P S1PR GVHD GVL mitochondrial fission

A Generalization of Eneström-Kakeya theorem and a Zero Free Region of a Polynomial

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Journal of Applied Mathematics and Physics 2021年第6期9卷 1271-1277页

作者： Mushtaq Ahmad Shah Ram Swroop Humayun Mohd sofi Insha Nisar G.C.E.t Safapora Ganderbal Kashmir Jammu and Kashmir India NIMS University Jaipur India Mewar University Rajasthan India

For the polynomial P (z) = ajzj, aj ≥ aj-1, a0 > 0, j = 1, 2, …, n, an > 0, a classical result of Eneström-Kakeya says that all the zeros of P (z) lie in |z|≤ 1. this result was generalised by A. Joyall and G. Labe... 详细信息

For the polynomial P (z) = t_***" alt="" />ajzj, aj ≥ aj-1, a0 > 0, j = 1, 2, …, n, an > 0, a classical result of Eneström-Kakeya says that all the zeros of P (z) lie in |z|≤ 1. this result was generalised by A. Joyall and G. Labelle, where they relaxed the non-negativity condition on coefficients. It was further generalized by M.A Shah by relaxing the monotonicity of some coefficients. In this paper, we use some known techniques and provide some more generalizations of the above results by giving more relaxation to the conditions.

关键词： Polynomial Zeros Eneström-Kakeya theorem

StING negatively regulates allogeneic t-cell responses by constraining antigen-presenting cell function

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Cellular & Molecular Immunology 2021年第3期18卷 632-643页

作者： Hee-Jin Choitaylor ticer Yongxia Wu Chih-Hang Anthony tang Corey Mealer David Bastian M.Hanief sofi Linlu tian Steven Schutt Hee-Jin Choi taylor ticer Mengmeng Zhang Xiaohui Sui Lei Huang Andrew L.Mellor Chih-Chi Andrew Hu Xue-Zhong Yu Microbiology&Immunology Medical University of South CarolinaCharlestonSCUSA Immunology Microenvironment&Metastasis ProgramThe Wistar InstitutePhiladelphiaPAUSA translational and Clinical Research Institute Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK Department of Medicine Medical University of South CarolinaCharlestonSCUSA Hollings Cancer Center Medical University of South CarolinaCharlestonSCUSA

Stimulator of interferon genes(StING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and ***,StING can also suppress tumor immunity and *** signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCt).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor t-cell priming during GVHD ***,how StING regulates host hematopoietic APCs after allo-HCt remains *** utilized murine models of allo-HCt to assess the role of StING in hematopoietic ***-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched *** bone marrow chimeras,we found that StING deficiency in host hematopoietic cells was primarily responsible for exacerbating the ***,StING on host CD11c+cells played a dominant role in suppressing allogeneic t-cell ***,StING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic ***,constitutive activation of StING attenuated the survival,activation,and function of APCs isolated from StING V154M knock-in ***-deficient APCs augmented donor t-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated *** pharmacologic approaches,we demonstrated that systemic administration of a StING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD *** conclusion,we revealed a novel role of StING in APC activity that dictates t-cell allogeneic responses and validated StING as a potential therapeutic target for controlling GVHD after allo-HCt.

关键词： Stimulator of interferon genes antigen-presenting cells allogeneic hematopoietic cell transplantation graft-versushost diseases hematopoietic stem-cell transplantation t cells

Innate-like CD4 t cells selected by thymocytes suppress adaptive immune responses against bacterial infections

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Open Journal of Immunology 2012年第1期2卷 25-39页

作者： Yu Qiao Brian M. Gray Mohammed H. sofi Laura D. Bauler Kathryn A. Eaton Mary X. D. O’Riordan Cheong-Hee Chang Department of Microbiology and Immunology University of Michigan Ann Arbor USA Unit for Lab Animal Medicine Medical School University of Michigan Ann Arbor USA

We have reported a new innate-like CD4 t cell population that expresses cell surface makers of effector/memory cells and produce th1 and th2 cytokines immediately upon activation. Unlike conventional CD4 t cells that are selected by thymic epithelial cells, these CD4 t cells, named t-CD4 t cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of t-CD4 t cells protected mice from airway inflammation suggesting an immune regulatory role of t-CD4 t cells. to further understand the function of t-CD4 t cells, we investigated immune responses mediated by t-CD4 t cells during bacterial infection because the generation of antigen specific CD4 t cells contributes to clearance of infection and for the development of immune memory. the current study shows a suppressive effect of t-CD4 t cells on both CD8 and CD4 t cell-mediated immune responses during Listeria and Helicobacter infections. In the mouse model of Listeria monocytogenes infection, t-CD4 t cells resulted in decreasedfrequency of Listeria-specific CD8 t cells and the killing activity of them. Furthermore, mice with t-CD4 t cells developed poor immune memory, demonstrated by reduced expansion of antigen-specific t cells and high bacterial burden upon re-infection. Similarly, the presence of t-CD4 t cells suppressed the generation of antigen-specific CD4 t cells in Helicobacter pylori infected mice. thus, our studies reveal a novel function of t-CD4 t cells in sup-pressing anti-bacterial immunity.

关键词： Bacterial Infection Innate-Like CD4 t Cells Immune Suppression

Comparative study of hypoglycemic and antibacterial activity of organic extracts of four Bangladeshi plants

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Journal of Coastal Life Medicine 2016年第3期4卷 231-235页

作者： Mohammad Shah Hafez Kabir Shabbir Ahmad Md.sofi Mahamoud Nishan Chakrabarty Md.Akramul Hoque Mohammed Munawar Hossain Md.Nazim Uddin Chy Mohammed Shoibe Department of Pharmacy International Islamic University ChittagongChittagongBangladesh

Objective:to examine hypoglycemic and antibacterial activity against some Gram-positive and Gram-negative bacteria of organic extracts of four Bangladeshi ***:An in vivo hypoglycemic effect on mice model was used to check the hypoglycemic effect of four Bangladeshi herbal organic extracts viz.,roots of Curculigo recurvata ***(Satipata)(***),leaf of Amorphophallus bulbifer Roxb.(Olkachu)(***),whole plant of thunbergia grandiflora Roxb.(Nillata)(***)and leaf of Steudnera colocasiifolia ***(Yunnan)(***)using glibenclamide as a positive control and water as a negative *** were also tested for antibacterial activity on three Grampositive and four Gram-negative bacteria by disk diffusion ***,*** and *** were extracted with methanol and *** was extracted with ***:Among all the plant extract,only ethanol extract of *** leaves at 800 mg/kg dose significantly(Pting glucose level in normal mice as compared to standard drug glibenclamide(5 mg/kg).Ethanol extract of *** leaves at 800 mg/kg dose decreased 20.28%of blood glucose level after 2 h of administration in normal mice,where glibenclamide decreased 39.63%.Methanol extract of *** didn’t show any zone of inhibition against the tested bacteria,but other three extracts showed a wide range of zone of ***,none of the extract showed antibacterial activity against all the tested *** extract of *** showed maximum zone of inhibition against Bacillus cereus[(10.50±0.50)mm],Salmonella typhi[(16.20±1.26)mm],Escherichia coli[(13.00±1.00)mm]and ethanol extract of *** showed maximum zone of inhibition against Staphylococcus aureus[(11.20±1.26)mm],Bacillus subtilis[(12.00±0.50)mm],Salmonella paratyphi[(10.80±0.29)mm].Only methanol extract of *** showed(8.50±0.50)mm and(7.20±0.76)mm zone of inhibition against P

关键词： Curculigo recurvata Steudnera colocasiifolia Hypoglycemic Antibacterial Disc diffusion method