Enhanced TCR-induced apoptosis in interferon regulatory factor 4-deficient CD4⁺ Th cells

Transcription factors of the interferon regulatory factor (IRF) family contribute to the regulation of cell proliferation and apoptosis. Here, we show that CD4⁺ T helper (Th) cells lacking IRF4 (IRF4^-/-) are highly sensitive to apoptosis. After infection of IRF4^-/- mice with the protozoan parasite Leishmania major, the lesion-draining lymph nodes developed the prototypic lymphadenopathy of wild-type mice after 4 wk, but demonstrated almost total loss of cellularity and enhanced apoptosis after 7 wk. In vitro, activation of IRF4^-/- CD4⁺ Th cells led to greatly increased apoptosis compared with wild-type cells. Coculture of IRF4^-/- and IRF4^+/+ CD4⁺ cells did not increase survival of IRF4^-/- CD4⁺ cells, indicating that the enhanced rate of IRF4^-/- Th cell apoptosis was neither transferable nor due to lack of a cytokine. Enhanced CD4⁺ cell apoptosis was also observed after anti-CD95 mAb treatment, despite normal CD95 expression. Removal of endogenous cytokines, notably interleukin (IL)-4, led to increased and equally high levels of IRF4^-/- and IRF4^+/+ cell apoptosis, whereas the protective activity of exogenous IL-4 was reduced in IRF4 ^-/- CD4⁺ cells despite normal expression of the IL-4 receptor. Therefore, IRF4 is central in protecting CD4⁺ cells against proapoptotic stimuli.