Patients with T cell large granular lymphocytic leukemia (T-LGL) often have expanded CD8 T cells clones bearing gain-of-function (GOF) somatic mutations in STAT3, and frequently develop autoimmune disease. In Immunity, Masle-Farquhar et al. find that STAT3 GOF somatic mutations in CD8 T cells are a cause, not an effect, of autoimmunity. In mouse models of human STAT3 GOF mutations, in which the mice developed splenomegaly and lymphadenopathy and succumbed to a wasting syndrome, there was an accumulation of CD8 T cells that expressed NKG2D and CX3CR1. This increase in CD8 T cells was mirrored in individuals with STAT3 GOF mutations. CD8+ T cells expressed genes associated with cytotoxicity and proliferation and were highly polyclonal. The CD8+ T cell accumulation was dependent on NKG2D and CD122 (also known as IL-15RB), and depletion of CD8+ T cells reduced inflammation and lethality in mice. Therefore, STAT3 GOF mutations can cause the accumulation of CD8 T cells, resulting in lethal pathology.