CTLA4 limits expansion of human cytotoxic CD4+ T cells to prevent B cell apoptosis

Abstract

Terminally differentiated CD8+ T cells are well described, whereas there remains considerable ambiguity about the definition of human terminally differentiated CD4+ T cells. CD57 is normally considered as a terminal differentiation marker for human T cells, but various features have been reported, including cytotoxicity, senescence or exhaustion. In this study, we first have shown that circulating CD57+ CD4+ T cells have a comprehensive cytotoxic transcriptome almost indistinguishable from CD8+ T cells and are enriched with various CD8+ T cell and cytotoxicity-related gene signatures. Second, we provide evidence that CTLA4 has a previously unappreciated function as an inhibitor of the acquisition of cytotoxicity by CD4+ T cells in terminal differentiation. Cytotoxicity of CD4+ T cells is increased in patients with CTLA4 haploinsufficiency, cancer patients after checkpoint inhibitors therapy and virus-infected mice with CTLA4 blockade. Granzyme+ CD4+ T cells, marked by TCF1 downregulation and formed in a proliferation-dependent manner, are also suppressed by soluble CTLA4-Ig in vitro. Third, circulating CD57+ CD4+ T cells are expanded in patients with primary antibody deficiency, a natural state of chronic infection, and further remarkably increased in CTLA4+/- patients. Lastly, circulating cytotoxic CD57+ CD4+ T cells cannot help B cells develop into plasmablast. Instead, we have shown that cytotoxic CD4+ T cells kill B cells via cytotoxicity, which might be responsible for the previously unexplained immunodeficiency with decreased immunoglobulins and B cells in CTLA4+/- patients. This risk appears to be offset in the germinal centre (GC), where Tfh cells are often CD57+ but express high levels of inhibitory receptors and fail to downregulate TCF1. In summary, we have elucidated a key aspect of human CD4+ T cell terminal differentiation. These findings explain the immunodeficiency in chronic infections and CTLA4 deficiency and provide potential new insights into checkpoint inhibitors therapy. Show more