Harberts Aenne, Schmidt Constantin, Schmid Joanna, Reimers Daniel, Koch-Nolte Friedrich, Mittrücker Hans-Willi, Raczkowski Friederike
Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16). doi: 10.1073/pnas.2014553118.
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 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced 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 cells) expressed higher IRF4 levels. Mice with constitutive knockout had diminished CD8 T-cell populations, and tamoxifen-induced 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 cells, in contrast, appear to depend on IRF4.
转录因子IRF4是CD8 T细胞激活、增殖并分化为效应细胞所必需的，因此对于强大的CD8 T细胞反应至关重要。IRF4在记忆性CD8 T细胞中的功能仍有待探索。为了研究IRF4在维持CD8记忆性T细胞分化状态和存活中的作用，我们使用了一种他莫昔芬诱导型敲除的小鼠模型，以排除由于缺乏IRF4导致记忆细胞分化效率低下所产生的影响。我们用卵清蛋白重组李斯特菌感染小鼠，并在病原体清除后诱导敲除。IRF4的缺失导致CD8记忆性T细胞发生表型变化，但并未导致记忆性T细胞总数减少。然而，再次遇到病原体时，CD8记忆性T细胞的扩增和效应功能的获得受损。与CD8效应记忆性T细胞相比，CD8组织驻留记忆性T细胞（T细胞）表达更高水平的IRF4。组成型敲除的小鼠CD8 T细胞群体减少，他莫昔芬诱导的缺失导致该细胞群体减少。总之，我们的结果表明，IRF4是CD8记忆性T细胞有效重新激活所必需的，但不是其总体存活所必需的。相比之下，CD8 T细胞的形成和维持似乎依赖于IRF4。
