Salmonella inhibits monocyte differentiation into CD11chiMHC-IIhi cells in a MyD88-dependent fashion

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-IIhi cells, in infected hosts. Ly6C(hi) monocytes, isolated from the blood of Salmonella-infected mice, developed into CD11c(hi)MHC-IIhi 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-IIhi cells. The bacteria-induced differentiation block was dependent on TLRs, as monocytes from MyD88(-/-) mice converted into CD11c(hi)MHC-IIhi 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-IIhi 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-IIhi cells with poor antigen-presentation capacity when cultured ex vivo, and that monocyte exposure to Salmonella inhibits their differentiation into CD11c(hi)MHC-IIhi cells in a MyD88-dependent fashion. J. Leukoc. Biol. 87: 823-832; 2010.