CCR2+ Inflammatory Monocytes Are Recruited to Yersinia pseudotuberculosis Pyogranulomas and Dictate Adaptive Responses at the Expense of Innate Immunity during Oral Infection

Murine Ly6C(hi) inflammatory monocytes (IMs) require CCR2 to leave the bone marrow and enter mesenteric lymph nodes (MLNs) and other organs in response to Yersinia pseudotuberculosis infection. We are investigating how IMs, which can differentiate into CD11c(+) dendritic cells (DCs), contribute to innate and adaptive immunity to Y. pseudotuberculosis. Previously, we obtained evidence that IMs are important for a dominant CD8(+) T cell response to the epitope YopE(69-77) and host survival using intravenous infections with attenuated Y. pseudotuberculosis. Here we challenged CCR2(+/+) or CCR2(-/-) mice orally with wild-type Y. pseudotuberculosis to investigate how IMs contribute to immune responses during intestinal infection. Unexpectedly, CCR2(-/-) mice did not have reduced survival but retained body weight better and their MLNs cleared Y. pseudotuberculosis faster and with reduced lymphadenopathy compared to controls. Enhanced bacterial clearance in CCR2(-/-) mice correlated with reduced numbers of IMs in spleens and increased numbers of neutrophils in livers. In situ imaging of MLNs and spleens from CCR2-GFP mice showed that green fluorescent protein-positive (GFP(+)) IMs accumulated at the periphery of neutrophil-rich Yersinia-containing pyogranulomas. GFP(+) IMs colocalized with CD11c(+) cells and YopE(69-77)-specific CD8(+) T cells in MLNs, suggesting that IM-derived DCs prime adaptive responses in Yersinia pyogranulomas. Consistently, CCR2(-/-) mice had reduced numbers of splenic DCs, YopE(69-77)-specific CD8(+) T cells, CD4(+) T cells, and B cells in organs and lower levels of serum antibodies to Y. pseudotuberculosis antigens. Our data suggest that IMs differentiate into DCs in MLN pyogranulomas and direct adaptive responses in T cells at the expense of innate immunity during oral Y. pseudotuberculosis infection.