Pachulec Emilia, Neitzke-Montinelli Vanessa, Viola João P B
Program of Cellular Biology, Brazilian National Cancer Institute (INCA) , Rio de Janeiro , Brazil.
Front Immunol. 2016 Oct 6;7:411. doi: 10.3389/fimmu.2016.00411. eCollection 2016.
Nuclear factor of activated T cells (NFAT) 2 null mutant mice die of cardiac failure, precluding analysis of the role of NFAT2 in lymphocyte responses. Only the NFAT2/Rag-1 chimeric mice model gave insight into the role of NFAT2 transcription factor in T lymphocyte development, activation, and differentiation. As reports are mainly focused on the role of NFAT2 in CD4 T lymphocytes activation and differentiation, we decided to investigate NFAT2's impact on CD8 T lymphocyte responses. We report that NFAT2 is phosphorylated and inactive in the cytoplasm of naive CD8 T cells, and upon TCR stimulation, it is dephosphorylated and translocated into the nucleus. To study the role of NFAT2 in CD8 T responses, we employed NFAT2CD4-Cre mice with NFAT2 deletion specifically in T cells. Interestingly, the absence of NFAT2 in T cells resulted in increased percentage of non-conventional innate-like CD8 T cells. These cells were CD122, rapid producer of interferon gamma (IFN-γ) and had characteristics of conventional memory CD8 T cells. We also observed an expansion of PLZF expressing CD3 thymocyte population in the absence of NFAT2 and increased IL-4 production. Furthermore, we found that CD8 T lymphocytes deficient in NFAT2 had reduced activation, proliferation, and IFN-γ and IL-2 production at suboptimal TCR strength. NFAT2 absence did not significantly influence differentiation of CD8 T cells into cytotoxic effector cells but reduced their IFN-γ production. This work documents NFAT2 as a negative regulator of innate-like CD8 T cells development. NFAT2 is required for complete CD8 T cell responses at suboptimal TCR stimulation and regulates IFN-γ production by cytotoxic CD8 T cells .
活化T细胞核因子（NFAT）2基因敲除突变小鼠死于心力衰竭，这使得对NFAT2在淋巴细胞反应中作用的分析无法进行。只有NFAT2/Rag-1嵌合小鼠模型有助于深入了解NFAT2转录因子在T淋巴细胞发育、激活和分化中的作用。由于报道主要集中在NFAT2在CD4 T淋巴细胞激活和分化中的作用，我们决定研究NFAT2对CD8 T淋巴细胞反应的影响。我们报道，在未活化的CD8 T细胞胞质中，NFAT2被磷酸化且无活性，而在TCR刺激后，它会去磷酸化并转移到细胞核中。为了研究NFAT2在CD8 T细胞反应中的作用，我们使用了在T细胞中特异性缺失NFAT2的NFAT2CD4-Cre小鼠。有趣的是，T细胞中NFAT2的缺失导致非传统的天然样CD8 T细胞百分比增加。这些细胞表达CD122，是干扰素γ（IFN-γ）的快速产生者，并具有传统记忆CD8 T细胞的特征。我们还观察到在没有NFAT2的情况下，表达PLZF的CD3胸腺细胞群体有所扩大，且IL-4产生增加。此外，我们发现NFAT2缺陷的CD8 T淋巴细胞在次优TCR强度下激活、增殖以及IFN-γ和IL-2产生均减少。NFAT2的缺失并未显著影响CD8 T细胞向细胞毒性效应细胞的分化，但降低了它们的IFN-γ产生。这项研究证明NFAT2是天然样CD8 T细胞发育的负调节因子。在次优TCR刺激下，完整的CD8 T细胞反应需要NFAT2，并且它可调节细胞毒性CD8 T细胞的IFN-γ产生。
