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cd8+t cell metabolic flexibility elicited by cd28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.tong Guanxi Qiao tiffany R.Emmons thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber Cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of technology BostonMA 02139USA Present address:Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of cd8+t-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of t cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature t cells.In doing so,we discovered a novel signaling axis that endows activated cd8+t cells with flexibility of glucose catabolism.ARS2 upregulation driven by cd28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of t-cell activation-induced alternative splicing events.Among these effects,the cd28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of cd8+t-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of cd28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in cd8+t cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

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A strategy for uncovering germline variants altering anti-tumor cd8 t cell response

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Journal of Genetics and Genomics 2023年第5期50卷 353-361页

作者： Vijay Kumar Ulaganathan Martina H.Vasileva Klinik fur Dermatologie&Allergology Universitatsmedizin GottingenGottingen 37075Germany Institut fuir Multiple Sklerose Forschung NeuroimmunologieUniversitatsmedizin GottingenGottingen 37075Germany University of Lorraine NGERE UnitFaculte de Medecine9 Avenue de La Foret de HayeVandoeuvre-les-Nancy 54505France

Among many factors known to alter the outcomes of t cell receptor(tCR)-induced proximal signaling,the role of human germline variants in dictating the individuality of the anti-tumor cd8 t cell response has remained challenging to address.Here,we describe a convenient strategy for molecular and functional characterization of phosphotyrosine-altering non-synonymous single nucleotide variations(ptyr-SNVs)that directly impact tCR-induced proximal phosphotyrosine motif-based signaling pathways.We devise an experimental co-cultivation set-up comprising a C57BL/6 mouse-derived metastatic melanoma cell line engineered to constitutively present ovalbumin(OVA)antigens and retrovirally engineered syngeneic major histocompatibility complex(MHC)Class I restricted OVA tCR-transgenic CD8 T cells(Ot-I).Using the synthetic version of ptyr-SNV rs1178800678-G/t-encoding integrin alpha 4(ItGA4)p.S1027I variant as a prototype,we show that under identical tCR stimulation conditions,genetically determined membrane-proximal immunoreceptor tyrosin activation motif(ItAM)results in increased tyrosine phosphorylation of 70 kDa zeta-chain-associated protein(ZAP70)and the levels of cytotoxic effector molecule granzyme B(GZMB),which in turn result in enhanced cytotoxic activity against metastatic melanoma cell line.this strategy paves the way for rapid molecular and functional characterization of anti-tumor immune response-linked germline ptyr-SNVs so as to improve our understanding of the genetic basis of individual-to-individual differences in anti-tumor cd8 t cell response.

关键词： Non-synonymous single nucleotide variants(nsSNVs) Membrane-proximal phosphotyrosine signalling motifs Phosphotyrosine-altering non-synonymous single nucleotide variants(ptyr-SNVs) Immunoreceptor tyrosine activation motif(ItAM) CD8 T cells Melanoma B16-F10

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cd4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with tacaribe arenavirus

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Cellular & Molecular Immunology 2017年第1期14卷 90-106页

作者： Derek DC Ireland Cecilia tami Joao Pedras-Vasconcelos Daniela Verthelyi Division of Biologics Review and Research-III Office of Biotechnology Center for Drug Evaluation and Research Food and Drug Administration Silver Spring MD 20993 USA

Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. the neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system （CNS） while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with tacaribe virus （tCRV） develop seizures, hindlimb paralysis and death within 15 days of inoculation. tCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, t cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific t cells fail to clear the virus but drive the disease, as t-cell-deficient cd3ε KO mice survive tCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with t-cell sufficient mice. cd8＋ t cells drive the pathology, which even in the absence of cd4＋ t-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. cd4＋ t cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after cd4＋ t-cell transfer. these data demonstrate distinct pathogenic effects of cd4＋ and cd8＋ t cells and identify them as possible therapeutic targets.

关键词： Astrocytes cd4 t cells CD8 T cells encephalitis Purkinje cells virus

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Long-term exposure to decabrominated diphenyl ether mpairs cd8 t-cell function in adult mice

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Cellular & Molecular Immunology 2014年第4期11卷 367-376页

作者： Weihong Zeng Ying Wang Zhicui Liu Asma Khanniche Qingliang Hu Yan Feng Weiyi Ye Jianglong Yang Shujun Wang Lin Zhou Hao Shen Yan Wang Shanghai Institute of Immunology Institute of Medical Sciences Shanghai Jiaotong University School of Medicine Shanghai China College of Public Health Shanghai Jiaotong University School of Medicine Shanghai China Department of Dermatology Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China Department of Microbiology University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Polybrominated diphenyl ethers （PBDEs） are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2＇,3,3＇,4,4＇,5,5＇,6,6＇-decabromodiphenyl ether （BDE-209） at doses of 8, 80 or 800 mg/kg of body weight （bw） at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine （IFN-7, IL-2 and tNF-a） production and lower cd8 t-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenesexpressing ovalbumin （rLm-OVA） and the OVA-specific CD8 T cells had reduced functionality. taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.

关键词： BDE-209 CD8 T cells continuous exposure immunotoxicity t-cell functions

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Regulatory t cells Suppress Pathogenic cd8(+)t cells in Primary Biliary Cirrhosis Mice Model

Regulatory T cells Suppress Pathogenic CD8(+)T cells in Prim...

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第九届全国免疫学学术大会

作者：王寅虎杨微廉哲雄中国科学技术大学

Primary Biliary Cirrhosis(PBC)is a female dominant progressive autoimmune liver disease characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts.Mice with t cell-restricted expression of a dominant negative form of transforming growth factorβreceptor typeⅡ(dntβRⅡ)spontaneously developed periductular aggregates in the liver.the precise relationship between the pathogenesis of PBC and regulatory t cells is poorly defined.Based on dntpRII mice,it was determined that the frequency of tregs didn’t change in lymph organs from dntpRII;Foxp3mice,compared with wild type(Foxp3)mice.cd4Foxp3tregs from dntβRⅡmice up-regulated suppressive functional molecule,such as cd25,CtLA-4,GItR,ICOS,cd69,and highly expressed th1 response or liver inflammation specific chemokine receptor CXCR3,meanwhile down-regulated cd62L(L-selectin),showed extremely activated phenotype.Besides,lacking of cd4t cells in dntβRⅡ:cd4mice aggravated PBC-like symptom compared with dntpRII mice.this data showed that in inflammatory milieu,regulatory t cells were over-activated.In the absence of cd4t cells,without the assistant from conventional cd4t cells and suppression from regulatory t cells,pathogenic t cells caused more severe liver inflammation.Moreover,Wt,dntpRII mice derived splenic tregs and in vitro tGF-P induced tregs(ti-tregs)showed obvious suppressive activity toward cd8t cells from dntβRⅡmice.Our research provided evidence for the protective role of regulatory t cells in this PBC mice model.After parabioted with wild type mice,dntβPⅡ:cd4mice showed almost no portal inflammation in liver and showed alleviated biliary disease.

关键词： Primary Biliary Cirrhosis Regulatory t cells CD8 T cells Bone marrow transplantation Parabiosis

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cdR3 repertoire diversity of cd8+ t lymphocytes in patients with HCV

CDR3 repertoire diversity of CD8+ T lymphocytes in patients ...

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第十三届全国免疫学学术大会

作者： Yu Ping Mengjia Song Meng Wanng Zhiqin Li Yi Zhang the First Affiliated Hospital of Zhengzhou University

t cell receptors(tCR) diversity is known to serve as a defining hallmark of the antigen-reactive t cell repertoire. Complementarity determining region 3(cdR3) was the most important region for the recognition of peptide-major histocompatibility complex(MHC) complexes and represented the diversity of tCR repertoire. In this study, we detected the cdR3 spectratypes by complexity scoring system to assess tCR repertoire diversity and further analyzed the correlation of cdR3 score with cd8 t cell function and with the prognosis of chronic hepatitis C virus(HCV)-infected patients. the results demonstrated that cdR3 score was related to cd8 t cell function and prognosis by analyzing the clinical indicators such as viral load(VL), rapid virologic response(RVR), early virologic response(EVR) and sustained virologic response(SVR). Importantly, we found that Vb27, a member of cdR3 subfamily, might play an important role in the clearance of HCV. these findings indicate that tCR diversity maybe serve as a biomarker to predict the clinical parameters of HCV-infected patients.

关键词： t cell receptor CD8 T cells Complementarity determining region 3 tCR diversity tCR repertoire

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mmunological functions of liver sinusoida endothelial cells

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Cellular & Molecular Immunology 2016年第3期13卷 347-353页

作者： Percy A Knolle Dirk Wohlleber Institute of Molecular Immunology and Experimental Oncology Klinikum Munchen rechts der Isar Technische Universitat Munchen Munchen 81675 Germany Institute of Experimental Immunology Universitatsklinikum Bonn Universitat Bonn Bonn Germany

Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen （cross）-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory t cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. the immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.

关键词： CD8 T cells cross-presentation liver LSEC

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