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the promise of γδ t cells and the γδ t cell receptor for cancer immunotherapy

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cellular & Molecular Immunology 2015年第6期12卷 656-668页

作者： Mateusz Legut David K Cole Andrew K Sewell Division of Infection and Immunity and Svstems Immunitv Universitv Research Institute. Cardiff University School of Medicine Cardiff UK

γδ t cells form an important part of adaptive immune responses against infections and malignant transformation. the molecular targets of humanγδt cell receptors （tCRs） remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the γδ t cell compartment in cancer immunosurveiliance and paving the way for the use of γδtCRs in cancer therapy. Ligand recognition by the γδ tCR often requires accessorylco-stimulatory stress molecules on both t cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike αβ t cells, γδ t cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human γδ t cells and discuss the promise of harnessing these cells for cancer treatment.

关键词： cancer γδ t cells immunotherapy phosphoantigens t cell receptor

Ssu72 is a t-cell receptor-responsive modifier that is indispensable for regulatory t cells

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cellular & Molecular Immunology 2021年第6期18卷 1395-1411页

作者： Jin-Kwan Lee Seo-Young Koo Hye-Mi Nam Jee-Boong Lee Jiwon Ko Kyung-Mo Kim Eun-Ji Park tae Jin Kim Ho Lee Heounjeong Go Chang-Woo Lee Research Institute Curogen TechnologySuwonSouth Korea Department of Molecular cell Biology Samsung Medical CenterSungkyunkwan University School of MedicineSuwonSouth Korea MOGAM Institute for Biomedical Research GyeonggiSouth Korea Department of Pathology Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea Asan Institute for Life Sciences Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea Department of Immunology Sungkyunkwan University School of MedicineSeoulSouth Korea Department of Cancer Biomedical Science Graduate School of Cancer Science and PolicyResearch InstituteNational Cancer CenterGyeonggiSouth Korea

the homeostatic balance between effector t cells and regulatory t cells(tregs)is crucial for adaptive immunity;however,epigenetic programs that inhibit phosphorylation to regulate treg development,peripheral expression,and suppressive activity are ***,we found that the Ssu72 phosphatase is activated by various t-cell receptor signaling pathways,including the t-cell receptor and IL-2R pathways,and localizes at the cell *** of Ssu72 in t cells disrupts CD4+t-cell differentiation into tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ,which induce CD4+t-cell activation and differentiation into effector cell *** also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in ***,Ssu72 forms a complex with PLCγ1,which is an essential effector molecule for t-cell receptor signaling as well as treg development and ***72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 ***,our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of treg cells in the periphery.

关键词： Ssu72 Regulatory t cells FoxP3 t cell receptor Autoimmunity

Regulation of t cell receptor signaling by cholesterol sulfate

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Regulation of T cell receptor signaling by cholesterol sulfa...

第十三届全国免疫学学术大会

作者： Feng Wang Center for Microbiota and Immunological Diseases Shanghai General HospitalShanghai Institute of ImmunologyShanghai Jiao Tong University School of Medicine

Most adaptive immune responses require the activation of specific t cells through the t cell receptor-CD3 complex(tCR). Previously, we found that cholesterol sulfate(CS), a naturally-occurring cholesterol metabolite, inhibits CD3 ItAM phosphorylation, a crucial first step in t cell activation. CS deficient mice exhibit a heightened sensitivity to a self-antigen during thymocyte development. Here we show that besides disrupting tCR multimers, CS can also regulate the conformation of tCR-CD3 leading to a change in secondary structure of CD3 cytoplasmic domains to block tCR signaling completely. Our results demonstrate that membrane CS bridges the gap between two fundamental tCR signaling models(clustering and conformational change). this novel regulatory role of sterol metabolite highlights the importance of the membrane microenvironment in modulating cell surface receptor activation.

关键词： t cell receptor lipid metabolism cholesterol sulfate

Partial recovery of disturbed V-J pairing profiles of t-cell receptor in people living with HIV receiving long-term antiretroviral therapy

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Science China(Life Sciences) 2021年第1期64卷 152-161页

作者： Guoli Li Jiarui Li Henghui Zhang Yu Zhang Di Liu Yu Hao Junyan Han Juan Du Liuluan Zhu Yongqin Zeng Bei Li Rui Li Chuan Song Fujie Zhang Chen Chen Hongxin Zhao Hui Zeng Institute of Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing100015China Beijing Key Laboratory of Emerging Infectious Diseases Beijing100015China Clinical and Research Center of Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing100015China Computational Virology Group Center for Bacteria and Virus Resources and ApplicationWuhan Institute of VirologyChinese Academy of SciencesWuhan430071China University of Chinese Academy of Sciences Beijing101408China

Chronic human immunodeficiency virus(HIV) infection not only causes a gradual loss of CD4~+t cells but also leads to a disturbance of the t cell receptor(tCR) repertoire. In people living with HIV(PLWH), monitoring tCR repertoire is challenged by the inconsistency of complementarity determining region 3(CDR3) and limited cell numbers in clinical samples. thus, a quantitative method is necessary for monitoring the tCR repertoire in *** characterized the tCR V-J pairing profile of na?ve and memory CD4~+t cells in healthy donors, HIV-infected antiretroviral therapy(ARt)-na?ve patients and long-term(over5 years) ARt-experienced patients by performing tCR sequencing. We developed a V-J index with 18 parameters which were subdivided into five categories(expression coverage, cumulative percentage of the top tenth percentile, diversity, intra-individual similarity and inter-individual similarity). In ARt-na?ve patients, 14 of the 18 parameters were significantly ***-term ARt recovered ten parameters. the four unrecovered parameters were related to inter-individual ***, these findings indicate that long-term ARt could only partially recover tCR V-J pairs and introduce newly impacted V-J pairs. Moreover, these results provide new insights into the V-J pairing of the tCR and into the disturbance of tCR repertoire in HIV infection.

关键词： acquired immune deficiency syndrome human immunodeficiency virus antiretroviral therapy t cell receptor V-J pairing

the Landscape of peripheral t cell receptor repertoire in autoimmune disease

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The Landscape of peripheral T cell receptor repertoire in au...

第十二届全国免疫学学术大会

作者： LIU Xiao LU Qianjin Zhang Wei Zhao Ming BGI-Shenzhen Hunan Key Laboratory of Medical Epigenomics the second Xiangya HospitalCentral South University

the pathogenesis of autoimmune disease,represented by systemic lupus erythematosus(SLE)and rheumatoid arthritis(RA),is thought to involve the auto-reactivity of circulating and tissue-resident t *** studies have been ... 详细信息

关键词： t cell receptor autoimmune disease

the repertoire features of t cell receptor β-chain at different age and gender groups in the healthy Chinese individuals

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The repertoire features of T cell receptor β-chain at diffe...

第十三届全国免疫学学术大会

作者： Jingyao Lian Feng Li Yi Zhang Biotherapy Center the First Affiliated Hospital Zhengzhou University

Aim: t cell immunity is dependent upon t cell receptor(tCR) recognition of large numbers of antigenic peptides presented in the context of major histocompatibility complex class I and II molecules. t cell repertoire describes lymphocytes characterized by tCR expression, which plays a pivotal role in antigen recognition. the tCR diversity and the combination of V with J gene is reflected in the t cell function and immune status. Our study aimed to investigate the t cell receptor β-chain repertoire changes with different age and gender in the Chinese individuals. the study explored the development and function of the immune system, as this could provide a theoretical basis for the treatment of immune-related diseases with ***: We analyzed the t cell receptor β-chain repertoire in 154 healthy Chinese individuals by High-throughput sequencing with age(age range: 6–70) and each age group of about 20 individuals(male and female).Results: the extent of t cell receptor diversity was not significantly different between gender groups but was significantly different between age groups. the t cell receptor diversity is decreased in the older people. We found the rearrangement of the V with J genes in t cell receptor β-chain which was highest between the ages of 21-30. We further identified the combination of V6-1 and J2-1 gene in t cell receptor β-chain with the highest expression over the human life span. In addition, the t cell receptor β complementarity-determining region 3 amino acid sequences were highest between the ages of ***: Our results showed the different features of t cell receptor β-chain repertoire in different age groups in the healthy Chinese individuals. In conclusion, it was expected that t cell receptor repertoires could serve as a useful tool for investigating the role of immune profiling in the healthy Chinese individuals.

关键词： t cell receptor Immunity Age High-throughput sequencing

Regulation of t cell receptor signaling by lipid metabolites

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Regulation of T cell receptor signaling by lipid metabolites

第十四届全国免疫学学术大会

作者： Feng Wang Shanghai Jiao tong University School of Medicine

Most adaptive immune responses require the activation of specific t cells through the t cell receptor-CD3 complex(tCR). Previously, we found that cholesterol sulfate(CS), a naturally-occurring cholesterol metabolite, inhibits CD3 ItAM phosphorylation, a crucial first step in t cell activation. CS deficient mice exhibit a heightened sensitivity to a self-antigen during thymocyte development. Here we show that besides disrupting tCR multimers, CS can also regulate the conformation of tCR-CD3 leading to a change in the secondary structure of CD3 cytoplasmic domains to block tCR signaling. Our Results demonstrate that membrane CS bridges the gap between two fundamental tCR signaling models(clustering and conformational change). this novel regulatory role of metabolite highlights the importance of the membrane microenvironment in modulating cell surface receptor activation. Moreover, our finding provides an opportunity to preform functional engineering on the tCR-CD3 complex for enhancing the ability of antigen recognition and boosting anti-tumor immunity of t cell.

关键词： t cell receptor lipid metabolite cholesterol sulfate antigen recognition anti-tumor immunity

Adaptive t cell immunotherapy in cancer

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Science China(Life Sciences) 2021年第3期64卷 363-371页

作者： Dongdong ti Miaomiao Bai Xiaolei Li Jianshu Wei Deyun Chen Zhiqiang Wu Yao Wang Weidong Han Bio-therapeutic Department Chinese PLA General HospitalBeijing 100853China

Impaired tumor-specific effector t cells contribute to tumor progression and unfavorable clinical outcomes. As a compensatoryt cell-dependent cancer immunoediting strategy, adoptive t cell therapy (ACt) has achieved encouraging therapeutic results,and this strategy is now on the center stage of cancer treatment and research. ACt involves the ex vivo stimulation and expansionof tumor-infiltrating lymphocytes (tILs) with inherent tumor reactivity or t cells that have been genetically modified to expressthe cognate chimeric antigen receptor or t cell receptor (CAR/tCR), followed by the passive transfer of these cells into alymphodepleted host. Primed t cells must provide highly efficient and long-lasting immune defense against transformed cellsduring ACt. Anin-depth understanding of the basic mechanisms of these living drugs can help us improve upon currentstrategies and design better next-generation t cell-based immunotherapies. From this perspective, we provide an overview ofcurrent developments in different ACt strategies, with a focus on frontier clinical trials that offer a proof of principle. Meanwhile,insights into the determinants of ACt are discussed, which will lead to more rational, potent and widespread applicationsin the future.

关键词： adoptive t cell therapy tumor-infiltrating lymphocytes chimeric antigen receptor t cell receptor

tCR–pMHC bond conformation controls tCR ligand discrimination

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cellular & Molecular Immunology 2020年第3期17卷 203-217页

作者： Dibyendu KSasmal Wei Feng Sobhan Roy Peter Leung Yanran He Chufan Cai Guoshuai Cao Huada Lian Jian Qin Enfu Hui Hans Schreiber Erin JAdams Jun Huang the Pritzker School of Molecular Engineering The University of ChicagoChicagoILUSA Department of Biochemistry and Molecular Biology The University of ChicagoChicagoILUSA Department of Pathology The University of ChicagoChicagoILUSA Department of Materials Science&Engineering Stanford UniversityStanfordCAUSA Department of Chemical Engineering Stanford UniversityStanfordCAUSA Section of cell&Developmental Biology Division of Biological SciencesUniversity of CaliforniaSan DiegoCAUSA

A major unanswered question is how a tCR discriminates between foreign and self-peptides presented on the APC ***,we used in situ fluorescence resonance energy transfer(FREt)to measure the distances of single tCR–pMHC bonds and the conformations of individual tCR–CD3ζreceptors at the membranes of live primary t *** found that a tCR discriminates between closely related peptides by forming single tCR–pMHC bonds with different conformations,and the most potent pMHC forms the shortest *** bond conformation is an intrinsic property that is independent of the binding affinity and kinetics,tCR microcluster formation,and CD4 *** bond conformation dictates the degree of CD3ζdissociation from the inner leaflet of the plasma membrane via a positive calcium signaling feedback loop to precisely control the accessibility of CD3ζItAMs for *** data revealed the mechanism by which a tCR deciphers the structural differences among peptides via the tCR–pMHC bond conformation.

关键词： Bond conformation t cell receptor Single molecule FREt ligand discrimination