Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle
Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle
复制标题
DOI：
10.1128/iai.00278-16
复制
发表时间：
2016-10-01
影响因子：
3.1
通讯作者：
Brown, Wendy C.
中科院分区：
文献类型：
--
作者：
Okagawa, Tomohiro;Konnai, Satoru;Brown, Wendy C.
CD 4（+）T细胞应答是控制牛边缘无形体感染的核心。然而，在用A.边缘外膜蛋白或纯化的外膜（OMs），这可能有助于这种立克次体的持续存在。在本研究中，我们假设感染后的T细胞耗竭是由T细胞上的免疫抑制受体如程序性死亡1（PD-1）和淋巴细胞活化基因3（LAG-3）的上调诱导的。在A中监测OM特异性T细胞应答和PD-1阳性（PD-1（+））LAG-3（+）耗尽的T细胞的动力学。先前用OM免疫的边缘病攻毒牛。与先前研究的数据一致，感染后5周（wpi），受攻击动物外周血单核细胞（PBMC）的OM特异性增殖和干扰素γ（IFN-γ）的产生受到显著抑制。此外，这些动物的菌血症和贫血也在第5周达到峰值。流式细胞术分析显示，PD-1（+）LAG-3（+）T细胞在CD 4（+）、CD 8（+）和δ γ T细胞群中的百分比逐渐增加，并在5 wpi达到峰值。还观察到LAG-3（+）γ δ T细胞百分比的大幅增加。重要的是，在体外，PD-1和LAG-3途径的联合阻断在5 wpi时部分恢复了OM特异性PBMC增殖和IFN-γ产生。综上所述，这些结果表明，PD-1和LAG-3在T细胞上的共表达有助于A.边缘特异性T细胞感染后，这些免疫抑制受体调节牛无形体病期间的T细胞反应。
The CD4(+) T-cell response is central for the control of Anaplasma marginale infection in cattle. However, the infection induces a functional exhaustion of antigen-specific CD4(+) T cells in cattle immunized with A. marginale outer membrane proteins or purified outer membranes (OMs), which presumably facilitates the persistence of this rickettsia. In the present study, we hypothesize that T-cell exhaustion following infection is induced by the upregulation of immunoinhibitory receptors on T cells, such as programmed death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3). OM-specific T-cell responses and the kinetics of PD-1-positive (PD-1(+)) LAG-3(+) exhausted T cells were monitored in A. marginale-challenged cattle previously immunized with OMs. Consistent with data from previous studies, OM-specific proliferation of peripheral blood mononuclear cells (PBMCs) and interferon gamma (IFN-gamma) production were significantly suppressed in challenged animals by 5 weeks postinfection (wpi). In addition, bacteremia and anemia also peaked in these animals at 5 wpi. Flow cytometric analysis revealed that the percentage of PD-1(+) LAG-3(+) T cells in the CD4(+), CD8(+), and delta gamma T-cell populations gradually increased and also peaked at 5 wpi. A large increase in the percentage of LAG-3(+) gamma delta T cells was also observed. Importantly, in vitro, the combined blockade of the PD-1 and LAG-3 pathways partially restored OM-specific PBMC proliferation and IFN-gamma production at 5 wpi. Taken together, these results indicate that coexpression of PD-1 and LAG-3 on T cells contributes to the rapid exhaustion of A. marginale-specific T cells following infection and that these immunoinhibitory receptors regulate T-cell responses during bovine anaplasmosis.