Allgäuer Andrea, Schreiner Elisabeth, Ferrazzi Fulvia, Ekici Arif B, Gerbitz Armin, Mackensen Andreas, Völkl Simon
Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany;
Institute of Human Genetics, University Hospital Erlangen, 91054 Erlangen, Germany.
J Immunol. 2015 Oct 1;195(7):3139-48. doi: 10.4049/jimmunol.1501389. Epub 2015 Aug 31.
Recently, a novel subset of TCRαβ(+) CD4(-) CD8(-) double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4(+) and CD8(+) T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4(+) effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.
最近，一种新型的TCRαβ(+) CD4(-) CD8(-)双阴性（DN）T细胞亚群被描述为在小鼠和人类中均能抑制免疫反应。此外，在小鼠模型中，输注和/或激活DN T细胞可特异性抑制同种异体反应性T细胞，并预防异基因造血干细胞移植后移植物抗宿主病的发生。我们证明，人类DN T细胞与其小鼠对应物一样，是CD4(+)和CD8(+) T细胞反应的高效抑制细胞。在造血干细胞移植和其他淋巴细胞减少的情况下，白细胞介素-7（IL-7）在T细胞区室的重建、存活和稳态中起重要作用。由于IL-7已被证明会干扰T细胞功能，我们询问IL-7是否会影响人类DN T细胞的功能。有趣的是，IL-7降低了DN T细胞对同种异体CD4(+)效应T细胞的抑制活性。有意思的是，我们的研究表明，IL-7激活了人类DN T细胞中的Akt/雷帕霉素机制靶点（mTOR）信号通路。重要的是，选择性抑制蛋白激酶Akt或mTOR可逆转IL-7的作用，从而恢复DN T细胞的功能，而抑制其他关键的T细胞信号通路则没有这种效果。进一步分析表明，IL-7/Akt/mTOR信号级联反应下调了与无反应相关的基因，并上调了与激活和增殖相关的因子，这些因子可能对DN T细胞功能至关重要。这些发现表明，IL-7和Akt/mTOR信号是DN T细胞抑制能力的关键因素。通过药物靶向这些信号通路可能会恢复和/或增强移植物抗宿主病中DN T细胞的功能。
