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

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外文摘要：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 pre-exhaustion 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.

外文关键词：

CTLA4ImmunodeficiencyCell exhaustionTerminal differentiationCytotoxic CD4+ T cellsCD57

作者：

Yuwei Hao、Bahar Miraghazadeh、Rochna Chand、Ainsley R.Davies、Chelisa Cardinez、Kristy Kwong、Morgan B.Downes、Rebecca A.Sweet、Pablo F.Ca?ete、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

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作者单位：

Centre for Personalised Immunology,John Curtin School of Medical Research,The Australian National University,Canberra,ACT,Australia

Translational Research Unit,The Canberra Hospital,Canberra,ACT,Australia

Division of Immunology and Infectious Diseases,John Curtin School of Medical Research,The Australian National University,Canberra,ACT,Australia

Department of Immunology,Fiona Stanley Hospital,Perth,WA,Australia

Department of Immunology,The Royal Children's Hospital,Melbourne,VIC,Australia

Department of Medical Oncology,The Canberra Hospital,Canberra,ACT,Australia

ANU Medical School,The Australian National University,Canberra,ACT,Australia

NHMRC Clinical Trials Unit,The University of Sydney,Sydney,NSW,Australia

The ACRF Biomolecular Resource Facility,John Curtin School of Medical Research,The Australian National University,Canberra,ACT,Australia

ANU Bioinformatics Consultancy,John Curtin School of Medical Research,The Australian National University,Canberra,ACT,Australia

Francis Crick Institute,1 Midland Rd,London NW1 1AT,UK.

Cambridge Institute of Therapeutic Immunology and Infectious Disease,University of Cam

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基金：

NHMRC grantsNHMRC grantsPrioritydrive Collaborative Cancer Research Scheme and funded by Cancer Australia

项目编号：

APP1113577APP1079648APP1130330

出版年：

2023

DOI：

10.1038/s41423-023-01027-8

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(7)

参考文献量94