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CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4^(+)T cells

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Cellular & Molecular Immunology 2023年第7期20卷 777-793页

作者： Yuwei Hao Bahar Miraghazadeh rochna chand Ainsley R.Davies Chelisa Cardinez Kristy Kwong Morgan B.Downes Rebecca A.Sweet Pablo F.Cañete Lloyd J.D’Orsogna David A.Fulcher Sharon Choo Desmond Yip Geoffrey Peters Sonia Yip Matthew J.Witney Maxim Nekrasov Zhi-Ping Feng David C.Tscharke Carola G.Vinuesa Matthew C.Cook Centre for Personalised Immunology John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia Translational Research Unit The Canberra HospitalCanberraACTAustralia Division of Immunology and Infectious Diseases John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia Department of Immunology Fiona Stanley HospitalPerthWAAustralia Department of Immunology The Royal Children’s HospitalMelbourneVICAustralia Department of Medical Oncology The Canberra HospitalCanberraACTAustralia ANU Medical School The Australian National UniversityCanberraACTAustralia NHMRC Clinical Trials Unit The University of SydneySydneyNSWAustralia The ACRF Biomolecular Resource Facility John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia ANU Bioinformatics Consultancy John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia Francis Crick Institute 1 Midland RdLondon NW11ATUK Cambridge Institute of Therapeutic Immunology and Infectious Disease University of CambridgeCambridgeUnited Kingdom.

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57^(+)CD4^(+)T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell RNA-seq analysis of matched CD57^(+)CD4^(+)T cells from blood and tonsil samples.Circulating CD57^(+)CD4^(+)T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8^(+)effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a preexhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57^(+)CD4^(+)T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4^(+)T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.

关键词： CTLA4 Immunodeficiency Cell exhaustion Terminal differentiation Cytotoxic CD4^(+)T cells CD57

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