Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells

The transcription factor IRF4 is required for CD8(+) T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8(+) T cell responses. The function of IRF4 in memory CD8(+) T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8(+) memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8(+) memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8(+) memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8(+) effector memory T cells, CD8(+) tissue-resident memory T cells (T-RM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8(+) T-RM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8(+) memory T cells. Formation and maintenance of CD8(+) T-RM cells, in contrast, appear to depend on IRF4.