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

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...

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Published in:Cellular & molecular immunology 2023-07, Vol.20 (7), p.777-793
Main Authors: Hao, Yuwei, Miraghazadeh, Bahar, Chand, Rochna, Davies, Ainsley R, Cardinez, Chelisa, Kwong, Kristy, Downes, Morgan B, Sweet, Rebecca A, Cañete, Pablo F, D'Orsogna, Lloyd J, Fulcher, David A, Choo, Sharon, Yip, Desmond, Peters, Geoffrey, Yip, Sonia, Witney, Matthew J, Nekrasov, Maxim, Feng, Zhi-Ping, Tscharke, David C, Vinuesa, Carola G, Cook, Matthew C
Format: Article
Language:English
Subjects:
Autoimmunity
B-Lymphocytes - metabolism
CD4 antigen
CD4-Positive T-Lymphocytes
CD57 antigen
CD57 Antigens - metabolism
CD8 antigen
Cell Differentiation
Chronic infection
CTLA-4 Antigen
CTLA-4 protein
Cytotoxicity
Effector cells
Germinal centers
Haploinsufficiency
Humans
Lymphocytes
Lymphocytes B
Lymphocytes T
Phenotypes
Transcriptomes
Transcriptomics
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Summary: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.
ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-023-01027-8