Prasad Sujata, Hu Shuxian, Sheng Wen S, Chauhan Priyanka, Singh Amar, Lokensgard James R
Department of Medicine, Neurovirology Laboratory, University of Minnesota, 3-107 Microbiology Research Facility, 689 23rd Avenue S.E., Minneapolis, MN, 55455, USA.
J Neuroinflammation. 2017 Apr 13;14(1):82. doi: 10.1186/s12974-017-0860-3.
Previous work from our laboratory has demonstrated that during acute viral brain infection, glial cells modulate antiviral T cell effector responses through the PD-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. Here, we evaluated the PD-1: PD-L1 pathway in development of brain-resident memory T cells (bT) following murine cytomegalovirus (MCMV) infection.
Flow cytometric analysis of immune cells was performed at 7, 14, and 30 days post-infection (dpi) to assess the shift of brain-infiltrating CD8 T cell populations from short-lived effector cells (SLEC) to memory precursor effector cells (MPEC), as well as generation of bT.
In wild-type (WT) animals, we observed a switch in the phenotype of brain-infiltrating CD8 T cell populations from KLRG1 CD127 (SLEC) to KLRG1 CD127 (MPEC) during transition from acute through chronic phases of infection. At 14 and 30 dpi, the majority of CD8 T cells expressed CD127, a marker of memory cells. In contrast, fewer CD8 T cells expressed CD127 within brains of infected, PD-L1 knockout (KO) animals. Notably, in WT mice, a large population of CD8 T cells was phenotyped as CD103 CD69, markers of bT, and differences were observed in the numbers of these cells when compared to PD-L1 KOs. Immunohistochemical studies revealed that brain-resident CD103 bT cells were localized to the parenchyma. Higher frequencies of CXCR3 were also observed among WT animals in contrast to PD-L1 KOs.
Taken together, our results indicate that bT are present within the CNS following viral infection and the PD-1: PD-L1 pathway plays a role in the generation of this brain-resident population.
我们实验室之前的研究表明，在急性病毒性脑感染期间，胶质细胞通过PD-1：PD-L1途径调节抗病毒T细胞效应反应，从而限制不受控制的神经炎症的有害后果。在此，我们评估了小鼠巨细胞病毒（MCMV）感染后脑驻留记忆T细胞（bT）发育过程中的PD-1：PD-L1途径。
在感染后7天、14天和30天进行免疫细胞的流式细胞术分析，以评估脑浸润CD8 T细胞群体从短期效应细胞（SLEC）向记忆前体效应细胞（MPEC）的转变，以及bT的生成。
在野生型（WT）动物中，我们观察到在从感染急性期到慢性期的转变过程中，脑浸润CD8 T细胞群体的表型从KLRG1⁺CD127⁻（SLEC）转变为KLRG1⁻CD127⁺（MPEC）。在感染后14天和30天，大多数CD8 T细胞表达CD127，这是记忆细胞的标志物。相比之下，在感染的PD-L1基因敲除（KO）动物的脑中，表达CD127的CD8 T细胞较少。值得注意的是，在WT小鼠中，大量CD8 T细胞的表型为CD103⁺CD69⁺，这是bT的标志物，与PD-L1基因敲除小鼠相比，这些细胞的数量存在差异。免疫组织化学研究表明，脑驻留的CD103⁺bT细胞定位于实质。与PD-L1基因敲除小鼠相比，WT动物中CXCR3的频率也更高。
综上所述，我们的结果表明，病毒感染后中枢神经系统中存在bT，且PD-1：PD-L1途径在这一脑驻留群体的生成中发挥作用。
