Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
J Leukoc Biol. 2010 May;87(5):823-32. doi: 10.1189/jlb.0909615.
Monocytes and DCs originate from a shared precursor in the bone marrow, and steady-state DCs in lymphoid organs develop directly from the precursor rather than via a monocyte intermediate. However, monocytes can differentiate into DCs in tissues such as the lung and gut mucosa and into macrophages in most tissues. As Ly6C hi monocytes accumulate in lymphoid organs during oral Salmonella infection, we investigated their ability to develop into potential DCs, identified as CD11c hi MHC-II hi cells, in infected hosts. Ly6C hi monocytes, isolated from the blood of Salmonella-infected mice, developed into CD11c hi MHC-II hi cells after culture with GM-CSF or Flt3L. In contrast, the same monocytes cultured in the presence of GM-CSF and heat-killed Salmonella did not differentiate into CD11c hi MHC-II hi cells. The bacteria-induced differentiation block was dependent on TLRs, as monocytes from MyD88-/- mice converted into CD11c hi MHC-II hi cells even in the presence of bacteria. We hypothesized that Salmonella-activated wild-type monocytes secreted mediators that inhibited differentiation of MyD88-/--derived monocytes. However, IL-6, IL-10, TNF-alpha, or IL-12p70 did not account for the inhibition. Finally, monocyte-derived CD11c hi MHC-II hi cells pulsed with OVA peptide or protein did not induce proliferation of antigen-specific CD4+ T cells but rather, suppressed the ability of DCs to activate CD4+ T cells. Overall, the data show that Ly6C hi monocytes from Salmonella-infected mice develop into CD11c hi MHC-II hi cells with poor antigen-presentation capacity when cultured ex vivo, and that monocyte exposure to Salmonella inhibits their differentiation into CD11c hi MHC-II hi cells in a MyD88-dependent fashion.
单核细胞和树突状细胞（DCs）起源于骨髓中的一个共同前体细胞，而淋巴器官中的稳态 DCs 直接从前体细胞发育而来，而不是通过单核细胞中间阶段。然而，单核细胞可以在肺部和肠道黏膜等组织中分化为 DCs，并在大多数组织中分化为巨噬细胞。由于 Ly6C hi 单核细胞在口腔沙门氏菌感染期间在淋巴器官中积累，我们研究了它们在感染宿主中发育为潜在 DCs（鉴定为 CD11c hi MHC-II hi 细胞）的能力。从感染沙门氏菌的小鼠血液中分离出的 Ly6C hi 单核细胞，在 GM-CSF 或 Flt3L 存在下培养后，可分化为 CD11c hi MHC-II hi 细胞。相比之下，在 GM-CSF 和热灭活的沙门氏菌存在下培养的相同单核细胞不会分化为 CD11c hi MHC-II hi 细胞。细菌诱导的分化阻断依赖于 TLR，因为即使在存在细菌的情况下，MyD88-/- 小鼠来源的单核细胞也会转化为 CD11c hi MHC-II hi 细胞。我们假设沙门氏菌激活的野生型单核细胞分泌了抑制 MyD88-/-衍生单核细胞分化的介质。然而，IL-6、IL-10、TNF-α 或 IL-12p70 并不能解释这种抑制作用。最后，用 OVA 肽或蛋白脉冲处理的单核细胞衍生的 CD11c hi MHC-II hi 细胞不会诱导抗原特异性 CD4+T 细胞增殖，而是抑制 DC 激活 CD4+T 细胞的能力。总体而言，数据表明，来自沙门氏菌感染小鼠的 Ly6C hi 单核细胞在体外培养时发育为 CD11c hi MHC-II hi 细胞，其抗原呈递能力较差，并且单核细胞暴露于沙门氏菌以 MyD88 依赖性方式抑制其分化为 CD11c hi MHC-II hi 细胞。
