XCR1 expression distinguishes human conventional dendritic cells type 1 with full effector functions from their immediate precursors

Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as non-lymphoid tissues. Steady state XCR1+ cDC1 display a pre-activated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1. 4 samples are analyzed, each sample of cDC1 steady state and R848 have one additional replicate (n=2)

树突状细胞（dendritic cells, DCs）是固有免疫与适应性免疫应答的主要调控因子。DCs可分为浆细胞样树突状细胞，以及1型与2型常规树突状细胞（conventional DCs, cDCs）。小鼠与人类的cDC1均表达XCR1的mRNA。小鼠相关研究揭示了XCR1-XCL1轴在免疫应答诱导中的特异性作用。本研究发现，人类cDC1可在淋巴组织及非淋巴组织中被区分为XCR1阴性（XCR1-）与XCR1阳性（XCR1+）两种亚群。相较于XCR1- cDC1，稳态状态下的XCR1+ cDC1呈现预激活表型。经刺激后，仅XCR1+ cDC1可分泌高水平的炎性细胞因子与趋化因子，这一特征与其介导的自然杀伤细胞（natural killer cells, NK cells）活化增强效应相关。此外，XCR1+ cDC1在抑制甲型流感病毒复制方面表现更优。进一步实验显示，在DC分化培养条件下，XCR1- cDC1可分化为XCR1+ cDC1；且在获得XCR1表达后，此类细胞的炎性细胞因子分泌水平可与XCR1+ cDC1相当。综上，XCR1是终末分化cDC1的标志物，可赋予人类cDC1抗病毒效应功能；而XCR1- cDC1或代表cDC1的晚期即刻前体细胞。本研究共分析4份样本，每份稳态状态的cDC1样本及R848处理样本均设有1个生物学重复（n=2）