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* Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48105; and
Department of Pathology and Laboratory Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI 48105
CCR4 is purported to be a Th type 2 (Th2) cell-biased receptor but its functional role is unclear. Recent studies suggest that chemokine receptor expression and function are more complex in vivo and raise doubts regarding restricted CCR4 expression by Th2 cells. To address these issues, we analyzed the role of CCR4 in highly polarized models of Th type 1 (Th1) and Th2 cell-mediated pulmonary granulomas, respectively, elicited by i.v. challenge of primed mice with either mycobacterial purified protein derivative or schistosomal egg Ag-coated beads. CCR4 agonists were expressed during both responses, correlating with a shift of CCR4+CD4+ T cells from blood to lungs. CCL22 dominated in draining nodes during the Th1 response. Analysis of CD4+ effector T cells revealed CCR4 expression and CCR4-mediated chemotaxis by both IFN-
and IL-4 producers. Studies of CCR4 knockout (CCR4–/–) mice showed partial impairment of the local type-2 cytokine response and surprisingly strong impairment of the Th1 response with abrogated IFN- production during secondary but not primary challenge. Adoptive transfer indicated CCR4–/–CD4+ Th1 cell function was defective but this could not be reconstituted with wild-type (CCR4+/+) CD4+ T cells indicating involvement of another CCR4+ population. Coculture of CCR4+/+CD4+ T cells and CCR4–/– dendritic cells revealed intact IL-2 but impaired IFN- production, pointing to a role for CCR4+ dendritic cells in effector cell expression. Therefore, CCR4 is not Th2-restricted and was required for sustenance and expression of the Th1 effector/memory response to mycobacterial Ags.
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1 This work was supported by National Institutes of Health–National Institute of Allergy and Infectious Diseases Grant A143460 and in part by Department of Veterans Affairs and National Institutes of Health Grants HL31237 and HL35276. Schistosomal life stages or materials for this work were supplied through National Institutes of Health–National Institute of Allergy and Infectious Diseases Contract NO1-AI-55270.
2 Address correspondence and reprint requests to Dr. Stephen W. Chensue, Pathology and Laboratory Medicine 113, Veterans Affairs Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105. E-mail address: schensue{at}umich.edu
3 Abbreviations used in this paper: Th1, Th type 1; Th2, Th type 2; DC, dendritic cell; PPD, purified protein derivative; SEA, schistosomal egg Ag; LCM, laser capture microdissection.
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