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

Cellular and Molecular Immunology · 21 authors, 12 centres

AI SUMMARY

FIDELITY 100%

POPULATIONHuman blood and tonsil samples from patients with primary antibody deficiency and CTLA4 haploinsufficiency, plus mice undergoing viral infection

INTERVENTIONCTLA4 haploinsufficiency or CTLA4 blockade (clinical/checkpoint inhibition context) and live viral infection in mice

COMPARISONHealthy donor blood/tonsil CD4+ subsets and uninfected/control mice

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

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TL;DR

Single-cell RNA-seq and functional assays of human blood and tonsil CD4+ T cells, plus a mouse viral infection model, identify a CTLA4-restrained cytotoxic CD4+ subset (CD4cyt) that is expanded in primary antibody deficiency and CTLA4 haploinsufficiency.

Full summary

973 CHARS

The study used matched human blood and tonsil samples plus a mouse viral infection model to dissect CD57+ CD4+ T-cell biology. Circulating CD57+ CD4+ T cells exhibited a cytotoxic transcriptome resembling CD8+ effector cells, could kill B cells in vitro, and inhibited B-cell responses. This CD4cyt population was expanded in patients with primary antibody deficiency and further increased with CTLA4 haploinsufficiency or blockade, consistent with CTLA4 restraining cytotoxic CD4+ formation. By contrast, tonsillar CD57+ germinal center Tfh showed a pre-exhaustion signature with high TCF7, TOX, and ID3 expression, constitutive CTLA4, and refractoriness to cytotoxicity even after CTLA4 inhibition. The authors propose that cytotoxicity and exhaustion features in CD57+ CD4+ T cells are compartmentalized between blood and germinal centers, and that CTLA4 is a key modifier of CD4+ cytotoxicity whose pathological effects are accentuated by chronic antigenic stimulation.

PICO

PPOPULATION

Human blood and tonsil samples from patients with primary antibody deficiency and CTLA4 haploinsufficiency, plus mice undergoing viral infection

IINTERVENTION

CTLA4 haploinsufficiency or CTLA4 blockade (clinical/checkpoint inhibition context) and live viral infection in mice

OOUTCOME

CD57+ CD4+ T-cell cytotoxic transcriptome, B-cell killing, and germinal center phenotype compartmentalization

STUDY TYPE

other

SPECIALTY

immunology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10166697

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

Cellular and Molecular Immunology

READ THE FULL PAPER

ABSTRACT

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.

CITATION EXPORT

Yuwei Hao, Bahar Miraghazadeh, Rochna Chand et al.. CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4+ T cells. Cellular and Molecular Immunology. (2023). https://doi.org/10.1038/s41423-023-01027-8

AUTHORS

21 · 12 CENTRES

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

1grid.1001.00000 0001 2180 7477Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
2grid.413314.00000 0000 9984 5644Translational Research Unit, The Canberra Hospital, Canberra, ACT Australia
3grid.1001.00000 0001 2180 7477Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
4grid.459958.c0000 0004 4680 1997Department of Immunology, Fiona Stanley Hospital, Perth, WA Australia
5grid.416107.50000 0004 0614 0346Department of Immunology, The Royal Children’s Hospital, Melbourne, VIC Australia
6grid.413314.00000 0000 9984 5644Department of Medical Oncology, The Canberra Hospital, Canberra, ACT Australia
7grid.1001.00000 0001 2180 7477ANU Medical School, The Australian National University, Canberra, ACT Australia
8grid.1013.30000 0004 1936 834XNHMRC Clinical Trials Unit, The University of Sydney, Sydney, NSW Australia
9grid.1001.00000 0001 2180 7477The ACRF Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
10grid.1001.00000 0001 2180 7477ANU Bioinformatics Consultancy, John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
11grid.451388.30000 0004 1795 1830Francis Crick Institute, 1 Midland Rd, London, NW1 1AT UK
12grid.5335.00000000121885934Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom