CCR4 Participation in Th Type 1 (Mycobacterial) and Th Type 2 (Schistosomal) Anamnestic Pulmonary Granulomatous Responses

Abstract

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-γ 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-γ 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-γ 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.

CC Chemokine Receptor 4 Contributes to Innate NK and Chronic Stage T Helper Cell Recall Responses during Mycobacterium bovis Infection

“…3 This finding was unexpected and provided further evidence that CCR4 expression and function were not restricted to Th2 cells. However, the role of CCR4 in the lung response to a live mycobacterial agent was unknown.…”

“…2 We demonstrated that CCR4ϩ Th1 and Th2 cells were detected in mouse models of Th1 and Th2 cell-mediated pulmonary granulomatous inflammation, respectively, elicited by mycobacterial and helminth antigens. 3 In a detailed analysis 4 of human peripheral blood T cells, CCR4 expression was detected on isolated human CD4 ϩ memory T cells with Th1 and Th2 characteristics. The specific ligands for CCR4, cysteine-cysteinyl ligan (CCL)17, and CCL22 induced migration of both Th1 and Th2 cells in vitro.…”

Pulmonary Mycobacterial Granuloma

“…23,24,26 Purified airway luminal and granuloma cells were stained with antibodies against CD3, CD4, CD8, CD19, CD11c, Gr.1, CD11b, or NK1.1 and analyzed by FACS. The FACS analysis revealed the presence of CD3ϩCD4 ϩ (CD4 T cells), CD3ϩCD8ϩ (CD8 T cells), CD3-CD19ϩ (B cells), CD3-NK1.1ϩ [natural killer (NK) cells], CD11cϩ-CD11bϩ/Ϫ (CD11cϩ APCs), CD11c-CD11bϩ (CD11bϩ APCs), and CD11c-Gr.1ϩ (neutrophils) cell populations in both the airway lumen and granuloma (Table 1).…”

Temporal Dynamic Changes of Phenotypic Expression of Peripheral CD4 Cells during Environmental Allergen Challenge in an Experimental Model of Canine Atopic Dermatitis: A Pilot Study

“…It has also been found that mRNA of CCL17 and its receptor CCR4 are primarily expressed in lesional skin of atopic dogs and are not detected in non-lesional canine skin [15]. Although the CCR4 receptor is preferentially expressed on T H 2 cells, other subsets including activated T H 1 cells have displayed expression of the same receptor [6].…”