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Identification and Characterization of Novel Bone Marrow Myeloid DEC205⁺Gr-1⁺ Cell Subsets That Differentially Express Chemokine and TLRs

Discovery Research, Centocor Research and Development, Radnor, PA 19355

Bone marrow-derived immunomodulatory cytokines impart a critical function in the regulation of innate immune responses and hemopoiesis. However, the source of immunomodulatory cytokines in murine bone marrow and the cellular immune mechanisms that control local cytokine secretion remain poorly defined. Herein, we identified a population of resident murine bone marrow myeloid DEC205⁺CD11c^–B220^–Gr1⁺CD8^–CD11b⁺ cells that respond to TLR2, TLR4, TLR7, TLR8, and TLR9 agonists as measured by the secretion of proinflammatory and anti-inflammatory cytokines in vitro. Phenotypic and functional analyses revealed that DEC205⁺CD11b⁺Gr-1⁺ bone marrow cells consist of heterogeneous populations of myeloid cells that can be divided into two main cell subsets based on chemokine and TLR gene expression profile. The DEC205⁺CD11b⁺Gr-1^low cell subset expresses high levels of TLR7 and TLR9 and was the predominant source of IL-6, TNF-, and IL-12 p70 production following stimulation with the TLR7 and TLR9 agonists CpG and R848, respectively. In contrast, the DEC205⁺CD11b⁺Gr-1^high cell subset did not respond to CpG and R848 stimulation, which correlated with their lack of TLR7 and TLR9 expression. Similarly, a differential chemokine receptor expression profile was observed with higher expression of CCR1 and CXCR2 found in the DEC205⁺CD11⁺Gr-1^high cell subset. Thus, we identified a previously uncharacterized population of resident bone marrow cells that may be implicated in the regulation of local immune responses in the bone marrow.

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¹ Address correspondence and reprint requests to Dr. M. Lamine Mbow, Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121. E-mail address: Lmbow{at}gnf.org

² Abbreviations used in this paper: DC, dendritic cell; CLR, C-type lectin receptor; poly(I:C), polyinosinic:polycytidylic acid; PGN, peptidoglycan.

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