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

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

doi:10.1038/s41423-023-01027-8

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

Cell Mol Immunol. 2023 Jul;20(7):777-793. doi: 10.1038/s41423-023-01027-8. Epub 2023 May 9.

Authors

Yuwei Hao^{1

2

3}, Bahar Miraghazadeh^{1

2

3}, Rochna Chand^{1

2

3}, Ainsley R Davies^{1

2

3}, Chelisa Cardinez^{1

2

3}, Kristy Kwong^{1

2

3}, Morgan B Downes^{1

2

3}, Rebecca A Sweet^{1

2

3}, Pablo F Cañete^{1

3}, Lloyd J D'Orsogna⁴, David A Fulcher³, Sharon Choo⁵, Desmond Yip^{6

7}, Geoffrey Peters^{6

7}, Sonia Yip⁸, Matthew J Witney³, Maxim Nekrasov⁹, Zhi-Ping Feng¹⁰, David C Tscharke³, Carola G Vinuesa^{1

3

11}, Matthew C Cook^{12

13

14

15

16}

Affiliations

¹ Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
² Translational Research Unit, The Canberra Hospital, Canberra, ACT, Australia.
³ Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
⁴ Department of Immunology, Fiona Stanley Hospital, Perth, WA, Australia.
⁵ Department of Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia.
⁶ Department of Medical Oncology, The Canberra Hospital, Canberra, ACT, Australia.
⁷ ANU Medical School, The Australian National University, Canberra, ACT, Australia.
⁸ NHMRC Clinical Trials Unit, The University of Sydney, Sydney, NSW, Australia.
⁹ The ACRF Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
¹⁰ ANU Bioinformatics Consultancy, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
¹¹ Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
¹² Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia. [email protected].
¹³ Translational Research Unit, The Canberra Hospital, Canberra, ACT, Australia. [email protected].
¹⁴ Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia. [email protected].
¹⁵ ANU Medical School, The Australian National University, Canberra, ACT, Australia. [email protected].
¹⁶ Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom. [email protected].

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.

Keywords: CD57; CTLA4; Cell exhaustion; Cytotoxic CD4+ T cells; Immunodeficiency; Terminal differentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes* / metabolism
CD4-Positive T-Lymphocytes*
CD57 Antigens / metabolism
CTLA-4 Antigen
Cell Differentiation
Humans

Substances

CD57 Antigens
CTLA-4 Antigen
CTLA4 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding