PD-1 regulates KLRG1+ group 2 innate lymphoid cells. Mus musculus

Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens, allergens, tissue remodeling and metabolic homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated but co-receptor mediated negative regulatory axis is yet to be defined. We demonstrate that PD-1 is an important negative regulator of KLRG1+ILC-2 function in both mice and humans. Increase in KLRG1+ ILC-2 cells numbers were attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1+ ILC-2 subsets occurred in pdcd1-/- mice and on adoptive transfer, pdcd1-/- KLRG1+ ILC-2s significantly reduced worm burden. Furthermore, blocking antibody to PD-1 increased KLRG1+ ILC-2 cell number and reduced disease burden. Therefore PD-1 is an important negative regulator and is vital for maintaining the number and hence function of KLRG1+ ILC-2s. Overall design: Microarray for wildtype and Pdcd1 knockout mice, each with three replicates

2型先天淋巴细胞（Group 2 innate lymphoid cells，ILC-2s）可响应细胞因子，调控机体针对病原体、过敏原、组织重塑及代谢稳态的免疫应答。此前已有研究阐明通过诱导性共刺激分子（ICOS）对ILC-2s的正向调控通路，但共受体介导的负调控轴尚未被明确界定。本研究证实，程序性死亡受体1（PD-1）是小鼠和人类体内杀伤细胞凝集素样受体G1（KLRG1）阳性ILC-2s功能的重要负调控因子。KLRG1阳性ILC-2s的细胞数量增加，源于PD-1信号通路的固有缺陷，该缺陷可导致信号转导与转录激活因子5（STAT5）的激活水平显著增强。在巴西日圆线虫（Nippostrongylus brasiliensis）感染过程中，PDCD1基因敲除（pdcd1-/-）小鼠体内的KLRG1阳性ILC-2亚群出现显著扩增；过继转移pdcd1-/- KLRG1阳性ILC-2s后，宿主体内的虫荷显著降低。此外，靶向PD-1的封闭性抗体可增加KLRG1阳性ILC-2的数量，并减轻疾病负荷。由此可见，PD-1是重要的负调控因子，对维持KLRG1阳性ILC-2的数量及其功能至关重要。实验设计：对野生型小鼠及PDCD1基因敲除小鼠进行基因芯片检测，每组设置3个生物学重复。