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CC Chemokine Ligand 2 and Its Receptor Regulate Mucosal Production of IL-12 and TGF- in High Dose Oral Tolerance ¹

R. William DePaolo^*, Barrett J. Rollins, William Kuziel and William J. Karpus^2,*

^* Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Dana Farber Cancer Institute, Harvard University School of Medicine, Boston, MA 02115; and Section of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712

Oral tolerance is the result of a complex immunoregulatory strategy used by the gut and its associated lymphoid tissues to render the peripheral immune system unresponsive to nonpathogenic proteins, such as food or commensal bacteria. The mechanism of oral tolerance induction and maintenance is not well understood. We have previously shown that the chemokine, CC chemokine ligand 2 (CCL2), is important for the induction and maintenance of oral tolerance. To address the role CCL2 plays in oral tolerance, we used both CCL2^-/- and CCR2^-/- mice. Cells from the spleen, mesenteric lymph nodes, and peripheral lymph nodes of CCL2^-/- and CCR2^-/- mice fed high doses of OVA showed robust proliferative responses compared with cells from Ag-fed wild-type mice. CCL2^-/- and CCR2^-/- mice also produced high amounts of Th1 cytokines such as IL-2 and IFN- and very low amounts of IL-4 and IL-10. The ability of APCs from the gut of CCL2^-/- and CCR2^-/- OVA-fed mice to stimulate an indicator T cell line was evaluated. APCs from the Peyer’s patch of OVA-fed knockout animals could induce a T cell response measured by an increase in proliferation and generation of IL-12 and IFN- with a concomitant reduction of TGF- compared with wild-type controls that did not induce a Th1 response. These data indicate that CCL2 and signaling through its receptor CCR2 is critical for the induction of oral tolerance by regulating Ag presentation leading to a disruption in the balance of inflammatory and regulatory cytokines.

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