Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor.
Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor.
复制标题
作者：
由杜氏利什曼原虫引起的内脏利什曼病（VL）的免疫学标志是严重的免疫抑制。然而，这种免疫功能障碍的分子基础仍然不明确。由于树突状细胞（DC）通常启动抗利什曼原虫免疫应答，我们研究了DC是否在L。donovani感染，并评估其在免疫抑制中的作用。据此，我们确定了L.多诺万尼在DC上。值得注意的是，目前还不清楚L。donovani激活或抑制DC。此外，还对L.在DC上的Donovani在很大程度上是不确定的。在这里，我们报告说，L。donovani通过T细胞免疫球蛋白和粘蛋白-3（TIM-3）受体传递抑制信号来抑制DC活化/成熟，从而抑制抗利什曼病免疫应答。L.事实上，donovani触发了DC中的TIM-3磷酸化，这反过来又招募并激活了非受体酪氨酸激酶Btk。Btk通过抑制NF-κB通路以IL-10依赖的方式抑制DC的活化/成熟。用TIM-3特异性封闭抗体或抑制TIM-3或下游效应子Btk的表达可使DC对L. donovani。连续转移实验进一步证明TIM-3介导的L. Donovani诱导的DC抑制在体内抗利什曼病免疫应答的抑制中起关键作用。这些发现确定TIM-3作为抗利什曼原虫免疫应答的新调节剂，并证明了与L. Donovani感染
An immunological hallmark of visceral leishmaniasis (VL), caused by Leishmania donovani, is profound immunosuppression. However, the molecular basis for this immune dysfunction has remained ill defined. Since dendritic cells (DCs) normally initiate antileishmanial immune responses, we investigated whether DCs are dysregulated during L. donovani infection and assessed its role in immunosuppression. Accordingly, we determined the regulatory effect of L. donovani on DCs. Notably, it is still unclear whether L. donovani activates or suppresses DCs. In addition, the molecular mechanism and the relevant receptor (or receptors) mediating the immunoregulatory effect of L. donovani on DCs are largely undefined. Here, we report that L. donovani inhibited DC activation/maturation by transmitting inhibitory signals through the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby suppressed antileishmanial immune responses. L. donovani in fact triggered TIM-3 phosphorylation in DCs, which in turn recruited and activated a nonreceptor tyrosine kinase, Btk. Btk then inhibited DC activation/maturation by suppressing the NF-κB pathway in an interleukin-10 (IL-10)-dependent manner. Treatment with TIM-3-specific blocking antibody or suppressed expression of TIM-3 or downstream effector Btk made DCs resistant to the inhibitory effects of L. donovani. Adoptive transfer experiments further demonstrated that TIM-3-mediated L. donovani-induced inhibition of DCs plays a crucial role in the suppression of the antileishmanial immune response in vivo. These findings identify TIM-3 as a new regulator of the antileishmanial immune response and demonstrate a unique mechanism for host immunosuppression associated with L. donovani infection.
登录
查看更多内容
墨西哥利什曼病感染对树突状细胞信号传导和功能的影响
影响因子：
3.8
作者：
Contreras I;Estrada JA;Guak H;Martel C;Borjian A;Ralph B;Shio MT;Fournier S;Krawczyk CM;Olivier M
通讯作者：
Olivier M
影响因子：
30.5
作者：
Chiba, Shigeki;Baghdadi, Muhammad;Akiba, Hisaya;Yoshiyama, Hironori;Kinoshita, Ichiro;Dosaka-Akita, Hirotoshi;Fujioka, Yoichiro;Ohba, Yusuke;Gorman, Jacob V.;Colgan, John D.;Hirashima, Mitsuomi;Uede, Toshimitsu;Takaoka, Akinori;Yagita, Hideo;Jinushi, Masahisa
通讯作者：
Jinushi, Masahisa
影响因子：
2.8
作者：
GESSNER, A;BLUM, H;ROLLINGHOFF, M
通讯作者：
ROLLINGHOFF, M
来自整个利什曼原虫抗原的鼻内疫苗可提供保护并诱导针对内脏利什曼病的特定免疫反应。
影响因子：
3.8
作者：
Helou DG;Mauras A;Fasquelle F;Lanza JS;Loiseau PM;Betbeder D;Cojean S
通讯作者：
Cojean S
影响因子：
8.6
作者：
Gabhann, Joan Ni;Spence, Shaun;Jefferies, Caroline A.
通讯作者：
Jefferies, Caroline A.