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

Abstract

Abstract As chronic antigenic stimulation from infection and autoimmunity are features 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 CD57+ CD4+ T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil. Circulating CD57+ CD4+ T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8+ effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset has a precursor of exhaustion transcriptomic signature marked by TCF7, TOX, ID3, and constitutive expression of CTLA4, and are robust to becoming cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T cell phenotypes of cytotoxicity and exhaustion are compartmentalized between blood and germinal centres. CTLA4 is a key modifier of CD4+ T cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated in CTLA4 deficiency by the environmental stimulus of infection.