The Francis Crick Institute
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CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4+ T cells.

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journal contribution
posted on 2023-06-29, 09:42 authored by 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
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.