TOX is a nuclear factor critical for thymic development of CD4+ thymocytes, natural killer and innate lymphoid cells. In post-thymic antigen-specific CD8+ T cells, TOX is highly expressed in settings of chronic antigen encounter such as cancer and chronic infection and required for the persistence of exhausted CD8+ T cells. The role of TOX in CD4+ T cells is less clear. Here, we show that TOX is critical for CD4+ type 1 helper T (TH1) cell differentiation. Gain-of-function and loss-of-function studies show that TOX induces TH1 cell-associated molecular programs that drive TH1 cell-like phenotypes and interferon-γ production. TOX expression in CD4+ T cells from individuals with cancer was associated with increased cytotoxicity, antitumor immunity and improved responses to immunotherapy, as well as pathogenic responses in autoimmune and inflammatory diseases in mice and humans. Thus, TOX has opposing functions in CD4+ versus CD8+ T cells: while TOX is associated with CD8+ T cell exhaustion and generally with poor responsiveness to immunotherapy, in CD4+ T cells TOX drives TH1 cell fate commitment and is associated with antitumor immunity and pathogenic autoimmune responses.
