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| Open AccessComplementarity-determining region clustering may cause CAR-T cell dysfunction
The challenge of designing chimeric antigen receptor (CAR)-T cells for cancer therapy is not limited to finding targetable cellular proteins, but also in optimising the effector properties. Here authors show that single-chain variable fragment targeting moieties could unpredictably prompt spontaneous CAR-T cell activation via CAR clustering, which argues for empirical screening for tonic signalling.
- Tina Sarén
- , Giulia Saronio
- & Magnus Essand
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Article
| Open AccessTumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
Here authors show that GDF15, a cytokine that is produced by cancer cells, prevents T cells from extravasation into the tumour microenvironment. Low availability of T cells in GDF-15-expressing tumours thus precludes effective immune therapy.
- Markus Haake
- , Beatrice Haack
- & Jörg Wischhusen
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Article
| Open AccessIKK2/NFkB signaling controls lung resident CD8+ T cell memory during influenza infection
CD8+ T resident memory (TRM) cells are important in protection against virus infection and NFκB signalling may function in this process. Here the authors use an inducible transgenic mouse models where T cell intrinsic NFκB levels can be increased or decreased which affects how CD8+ TRM cells seed into the lungs after influenza infection.
- Curtis J. Pritzl
- , Dezzarae Luera
- & Emma Teixeiro
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Article
| Open AccessVγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males
Traumatic brain injury is not only a neurological but also an immunological condition in which multiple innate and adaptive immune cell types play roles. Here authors show in a mouse model that the Vγ4 subtype of the unconventional gamma-delta T cells promote neuroinflammation, while the Vγ1 subtype ameliorates immunopathology.
- Hadi Abou-El-Hassan
- , Rafael M. Rezende
- & Howard L. Weiner
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Article
| Open AccessCombined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells
T cell development requires functionally diverse thymic epithelial cell (TEC) populations performing specific functions. Here, using massively parallel flow cytometry and machine learning, the authors examine in mice the TEC compartment from the perinatal period to adulthood, identify novel phenotypic markers and characterize the function of perinatal cortical TEC.
- Fabian Klein
- , Clara Veiga-Villauriz
- & Georg A. Holländer
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Article
| Open AccessT cell receptor signaling strength establishes the chemotactic properties of effector CD8+ T cells that control tissue-residency
CD8+ T cells are found within peripheral tissues including the skin. Here, the authors use an interferon-gamma reporter system and viruses expressing agonistic peptides of varying affinities to investigate how T cell receptor signaling strength changes the chemotactic properties of effector CD8+ T cells to promote tissue-residency.
- Mahmoud Abdelbary
- , Samuel J. Hobbs
- & Jeffrey C. Nolz
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Article
| Open AccessDifferentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis
Interleukin 26 (IL-26) has been shown to have antimicrobial and pro-inflammatory effects. Here the authors establish a role for IL-26 in the generation of IL-17A producing Th17 CD4+ T cells and suggest it involves epithelial cross talk in skin lesions of psoriasis patients.
- Anissa Fries
- , Fanny Saidoune
- & Michel Gilliet
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Article
| Open AccessImmunological imprinting of humoral immunity to SARS-CoV-2 in children
The immune responses to SARS CoV-2 infection in children are less well understood than in adults. Here the authors characterise immune responses to newer omicron lineages and relate these to previous infection with earlier lineages of SARS-CoV-2, implicating a reduced immunogenicity from omicron variants and imprinting from previous virus strains.
- Alexander C. Dowell
- , Tara Lancaster
- & Paul Moss
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Article
| Open AccessAge-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade
Age-associated B cells (ABC) have been shown to be associated with autoimmunity and ageing. Here the authors examine whether ABC are transcriptionally or functionally altered in participants with reduced immune cell function and show that, being transcriptionally similar, high pre-vaccine levels are associated with poor vaccine response.
- Juan Carlos Yam-Puc
- , Zhaleh Hosseini
- & James E. D. Thaventhiran
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Article
| Open AccessNBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells
NBEAL2 loss of function mutations lead to grey platelet syndrome, a condition characterised by α-granule-deficient platelets and, in a proportion of cases, by autoimmunity. Here authors show that NBEAL2 physically interacts with CTLA-4 in human T cells, and NBEAL2 deficiency leads to reduced CTLA-4 surface expression in effector T cells, but not regulatory T cells, thus tipping the balance towards autoimmunity.
- Laure Delage
- , Francesco Carbone
- & Frédéric Rieux-Laucat
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Article
| Open AccessATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion
The ATR kinase has essential functions apart from its role in DNA replication stress. Here the authors find that in mouse primary B cells ATR tempers the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
- Demis Menolfi
- , Brian J. Lee
- & Shan Zha
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Article
| Open AccessSpatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate
It is debated how follicular helper T (Tfh) cells versus central memory CD4+ T cells arise from similar precursors, and little is known about the regulation of germinal-centre (GC)-Tfh cell differentiation. Here, authors establish markers in the early precursor stage that distinguish between the GC-Tfh and memory T cell fates and identify an important mechanism that regulates the competitive fitness of the GC-Tfh cells.
- Fangming Zhu
- , Ryan J. McMonigle
- & Hui Hu
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Article
| Open AccessSEC-seq: association of molecular signatures with antibody secretion in thousands of single human plasma cells
Linking proteins secreted from individual cells with other cellular information is challenging. Here, authors report a high-throughput method which uses hydrogel nanovials loaded with single cells to link the secretion profile of individual cells with their surface markers and transcriptomic data.
- Rene Yu-Hong Cheng
- , Joseph de Rutte
- & Richard G. James
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Article
| Open AccessVaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response
Protective immunity against SARS-CoV-2 relies on both antibodies and a T cell dependent response, however, direct experimental evidence for the contribution of cellular immunity is limited. Here authors present a mouse model that is susceptible to SARS-CoV-2 and lacks B cells to demonstrate the emergence of efficient cellular immune response against SARS-CoV-2 upon vaccination or viral challenge.
- Xiaolei Wang
- , Terrence Tsz-Tai Yuen
- & Jian-Dong Huang
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Article
| Open AccessB cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma
B cells are playing an active role in shaping the tumour immune microenvironment and the anti-tumour immune response in melanomas. Here authors show that intra-tumoral B cells are aberrantly activated and produce antibodies that are potentially autoreactive.
- Silvia Crescioli
- , Isabel Correa
- & Sophia N. Karagiannis
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Article
| Open AccessNeoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors
Tumor neoantigens versus tumor-associated antigens may have different functions in antitumor immunity depending on the strength of antigen recognition. Here the authors characterize CD8 T cell clones specific for TAA, neoantigens or viral antigens isolated from tumor and blood and show that neoantigen-specific clones have a higher structural avidity than TAA-specific ones and preferentially infiltrate tumors.
- Julien Schmidt
- , Johanna Chiffelle
- & Alexandre Harari
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Article
| Open AccessGrowth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation
Endocrine factors have been shown to alter functions of pathogenic Th17 cells that are involved in autoimmunity. Here the authors study the influence of growth hormone releasing hormone receptor and show that this receptor is found on Th17 cells and promotes ocular autoimmunity.
- Lin Du
- , Bo Man Ho
- & Wai Kit Chu
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Article
| Open AccessMolecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide
Cytotoxic lymphocytes (CTL) are important in the control of HIV and some HLA alleles are associated with protection or susceptibility to disease. Here the authors characterise an epitope where variants bind to HLA-B57 or HLA-B53 and they characterise the structural and functional TCR recognition differences.
- Xiaolong Li
- , Nishant Kumar Singh
- & Jia-huai Wang
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Article
| Open AccessMicrobiota-assisted iron uptake promotes immune tolerance in the intestine
Iron deficiencies are a common non intestinal symptom seen in patients with irritable bowel disease. Here the authors show an associative link between microbiota assisted uptake of nutrients including iron and the promotion of immune tolerance in the intestine.
- Lizhen Zhu
- , Geng Li
- & Xing Chang
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Article
| Open AccessCatch bond models may explain how force amplifies TCR signaling and antigen discrimination
Catch bonds where lifetime increases with force applied can form when T cell receptors (TCR) interact with agonist peptide-MHC (pMHC) complexes. Here the authors use a modelling and experimental approach to analyse 55 TCR–pMHC bond lifetime curves measured under force to further characterise the structural bases and functional relevance of catch bonds.
- Hyun-Kyu Choi
- , Peiwen Cong
- & Cheng Zhu
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Article
| Open AccessDelayed generation of functional virus-specific circulating T follicular helper cells correlates with severe COVID-19
T follicular helper cells (Tfh) enhance antibody responses and can circulate or be resident in lymph nodes. Here the authors show that during acute SARS-CoV-2 infection, circulating Tfh cells correlate with antibody titres and plasmablast levels but in more severe COVID-19 cases, cTfh generation is delayed.
- Meng Yu
- , Afandi Charles
- & Anna Smed-Sörensen
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Article
| Open AccessEmbryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla
Although the importance of thymic epithelial cells (TEC) in thymus physiology is established, the development of functionally diverse TEC populations remains incompletely understood. Here, using fate-mapping experiments in the embryonic thymus, the authors identify keratin19+ multipotent progenitor cells that support medullary TEC diversity in adulthood.
- Beth Lucas
- , Andrea J. White
- & Graham Anderson
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Article
| Open AccessLow-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells
The dysfunction of IL-10 secreting regulatory B cells has been linked to the pathogenesis of autoimmune disease. Here the authors show that low dose IL-2 therapy can enhance IL-10 production in regulatory B cell populations via the modulation of BACH2.
- Akimichi Inaba
- , Zewen Kelvin Tuong
- & Menna R. Clatworthy
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Article
| Open AccessExpansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice
IL-2 complexes (IL-2c) which are IL-2 complexed with anti-IL-2 can be used to promote T cell function. Here authors use IL2c in addition to checkpoint inhibitors and irradiation to increase anti-tumour T cell responses and promote tumour rejection in mouse cancer models.
- Kateryna Onyshchenko
- , Ren Luo
- & Gabriele Niedermann
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Article
| Open AccessLimited induction of polyfunctional lung-resident memory T cells against SARS-CoV-2 by mRNA vaccination compared to infection
Resident memory T cells at the respiratory tract may play critical roles in the response to respiratory infections including SARS-CoV-2. Here the authors characterise the lung resident T cell response generated in response to mRNA vaccination of SARS-CoV-2 Spike or in convalescent patients after natural infection. They show reduced frequency and functionality of tissue resident T cells in vaccinated versus convalescent patients which may impact disease control and vaccination strategies.
- Daan K. J. Pieren
- , Sebastián G. Kuguel
- & Meritxell Genescà
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Article
| Open AccessThe RNA-binding protein hnRNP F is required for the germinal center B cell response
The germinal centre (GC) response is characterized by regulated production of high affinity, class-switched antibodies in response to T-cell dependent antigens. Here authors show that the GC response is not only regulated at the transcriptional and protein levels, but also by the RNA-binding protein hnRNP F via alternative splicing of the co-stimulatory molecule CD40.
- Hengjun Huang
- , Yuxing Li
- & Xijun Ou
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Article
| Open AccessEarly life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis
Liver-resident natural killer cells develop locally and have multiple immunological roles in situ. Here the authors investigate the gut-liver axis and show the impact of the intestinal microbiota on the development of liver-resident natural killer cells.
- Panpan Tian
- , Wenwen Yang
- & Xiaohong Liang
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Article
| Open AccessAiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity
The regulation and direction of CD4+ T cells into phenotypic and functional lineages is coordinated by a complex set of mechanisms. Here the authors show a role for Aiolos as a regulator of the CD4+ cytotoxic and T follicular helper lineages.
- Kaitlin A. Read
- , Devin M. Jones
- & Kenneth J. Oestreich
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Article
| Open AccessAntigen discrimination by T cells relies on size-constrained microvillar contact
T cells can use TCR on microvilli to interact with peptide-MHC (pMHC) complexes on antigen presenting cells. Here the authors characterise how T cells use microvilli to interrogate reconstituted membranes for pMHC complexes and how this is regulated by a balance between glycoproteins/glycocalyces that reduce detection, and the small adhesion protein CD2, which enhances detection.
- Edward Jenkins
- , Markus Körbel
- & David Klenerman
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Article
| Open AccessB cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation
Class switch recombination (CSR) is a process by which B cells switch their immunoglobulin isotype and develop pathogen-eliminating antibodies. Here, the authors show that a protein kinase DYRK1A is required for protection from viral infection through the regulation of CSR and effective clonal expansion.
- Liat Stoler-Barak
- , Ethan Harris
- & Ziv Shulman
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| Open AccessControl of human cytomegalovirus replication by liver resident natural killer cells
Natural killer cells play important roles in the immune response to human cytomegalovirus infection. Here the authors implicate donor-derived liver resident natural killer cells in the control of human cytomegalovirus infection by analysis of perfusates derived from human transplant livers.
- Calum Forrest
- , Thomas J. G. Chase
- & Matthew Reeves
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Article
| Open AccessBiased IL-2 signals induce Foxp3-rich pulmonary lymphoid structures and facilitate long-term lung allograft acceptance in mice
IL-2/anti-IL-2 antibody complexes have been shown to facilitate the process of graft acceptance in transplantation. Here the authors use a mouse allograft model to show that IL-2 complexes promote graft acceptance and formation of inducible lymphoid structures containing Treg cells in transplanted lungs.
- Yoshito Yamada
- , Tuan Thanh Nguyen
- & Onur Boyman
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Article
| Open AccessInhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment
m6A modification has been reported to play roles in many developmental and pathological processes, but its role in AKI remains poorly understood. Here, the authors show the role and the mechanism of the m6A demethylase, ALKBH5 on IRI induced AKI.
- Juntao Chen
- , Cuidi Xu
- & Tongyu Zhu
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Article
| Open AccessItaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming
Dysregulation of T cell homeostasis is known to contribute to the immunopathology of autoimmune diseases. Here the authors show that itaconate impacts autoimmune pathology by altering T cells via modulation of metabolic and epigenetic programs.
- Kuniyuki Aso
- , Michihito Kono
- & Tatsuya Atsumi
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Article
| Open AccessPhenotypic characterization of single CD4+ T cells harboring genetically intact and inducible HIV genomes
Some HIV-infected cells persist during antiretroviral therapies (ART) but their phenotype is less clear. Dufour et al. show that HIV-infected cells that persist in people receiving ART are phenotypically diverse and that CD4+ T cells expressing the integrin VLA-4 are highly enriched in replication-competent HIV.
- Caroline Dufour
- , Corentin Richard
- & Nicolas Chomont
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Article
| Open AccessLong non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response
Long noncoding RNA molecules are RNA transcripts long thought to remain untranslated. In this study, the authors demonstrate that certain lncRNA can be translated into peptides that are immunogenic to CD8+ T cells and promote anti-tumour responses when delivered as vaccine vectors in mice.
- Wojciech Barczak
- , Simon M. Carr
- & Nicholas B. La Thangue
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Article
| Open AccessProlonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys
HIV infection results in the depletion of CD4+ T cells overtime and the loss of coordinated cellular immunity, but how this corresponds to the SIV infected African Green Monkey (AGM) model of non-progressive disease is not known. Here the authors assess the impact of experimental CD4+ T cell depletion in AGM and show that lack of disease progression and resistance to AIDS in this model are independent of CD4+ T cell loss.
- Quentin Le Hingrat
- , Paola Sette
- & Ivona Pandrea
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Article
| Open AccessNsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis
Th17 cells produce a range of characteristic Th17 type cytokines and express transcription factors governed by epigenetic regulation to engage the Th17 programme. Here the authors implicate the RNA 5- methylcytosine (m5C) methyltransferase Nsun2 in Th17 cells and the promotion of colitis in a murine model.
- Wen-Lan Yang
- , Weinan Qiu
- & Yun-Gui Yang
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Article
| Open AccessFGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells
Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.
- Qingnan Zhao
- , Jiemiao Hu
- & Shulin Li
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Article
| Open AccessMyelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation
Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.
- Maxime Boy
- , Valeria Bisio
- & Nicolas Dulphy
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Article
| Open AccessG9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma
Engineered T cells are used for tumour immunotherapy but can have side effects and need multiple treatment rounds. Here during expansion of T cells from patients, the authors use an inhibitor of the epigenetic regulator G9a/GLP and show that this increases T cell cytotoxic function and tumour reduction in vitro and in vivo respectively.
- Maxine S. Y. Lam
- , Jose Antonio Reales-Calderon
- & Andrea Pavesi
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Article
| Open AccessGermline T cell receptor exchange results in physiological T cell development and function
The currently available transgenic T cell receptor (TCR) models represent high affinity antigen-TCR interactions. Authors here present an alternative approach to target an exogenous TCR into the physiological Trac locus in the germline of mice, which uncovers that the natural genomic context for TCRs can enhance the antigen sensitivity of lower affinity TCRs and enables the physiologic range of antigen-TCR interaction and a gene dosage dependent mechanism of central tolerance.
- Meagan R. Rollins
- , Jackson F. Raynor
- & Ingunn M. Stromnes
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Article
| Open AccessIFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells
IFN-γ is associated with the efficacy of anti-tumour immune responses, and both pro- and anti-tumour functions have been ascribed to this cytokine. Here, the authors demonstrate that IFN-γ signalling inhibits the maintenance of stem-like T cells, thereby impairing anti-tumour immune responses.
- Julie M. Mazet
- , Jagdish N. Mahale
- & Audrey Gérard
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Article
| Open AccessCytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis
The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB+ CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing.
- Jae-Seung Moon
- , Shady Younis
- & William H. Robinson
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Article
| Open AccessCD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment
The presence of classical type 1 dendritic cells (cDC1) positively influences prognosis in cancer, but their intricate networking with the various T cell types found in the tumour microenvironment is not fully appreciated. Here the authors show that cDC1 encounter with CD4+ helper T-cells transforms their gene expression signature, and these “helped” dendritic cells enable the function of anti-tumour cytotoxic T-cells.
- Xin Lei
- , Indu Khatri
- & Yanling Xiao
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Article
| Open AccessTranslation factor eIF5a is essential for IFNγ production and cell cycle regulation in primary CD8+ T lymphocytes
The translational elongation factor eIF5a may have a function in T cell protein translation. Here the authors show that hypusination of eIF5a or deletion of eIF5a alters the profile of mRNA translation in T cells and that eIF5 regulates the proliferation and effector function of these T cells.
- Thomas C. J. Tan
- , Van Kelly
- & Rose Zamoyska
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Article
| Open AccessDysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19
Cytotoxic T lymphocytes play important roles in the anti-viral immune response in COVID-19, and it is important to know how they contribute to disease outcome. Authors here identify a dominant SARS-CoV-2 M protein epitope, M198–206, and show that M198–206-specific cytotoxic T cells from convalescent patients with severe disease harbour a gene expression pattern indicative of poor functionality.
- Hideki Ogura
- , Jin Gohda
- & Satoshi Ishido
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Article
| Open AccessSingle-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity
Knowledge of the transcriptional programs of human kidney cell populations at homeostasis is limited. Here, the authors show sex-based differences in gene expression of kidney parenchymal cells and examine the complexity of kidney-resident immune cells using single cell RNA sequencing of healthy living kidney donors.
- Caitriona M. McEvoy
- , Julia M. Murphy
- & Sarah Q. Crome
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Article
| Open AccessIdentification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection
The early immune response following exposure to HCV is not fully explored. Here the authors use single cell analysis and immune profiling to relate the infection sequence and immune response to early HCV infection showing that exhausted phenotypes of T cells arise early post infection.
- Curtis Cai
- , Jerome Samir
- & Fabio Luciani