CCR8 is expressed by antigen-elicited, IL-10-producing CD4+CD25+ T cells, which regulate Th2-mediated granuloma formation in mice.
CCR8 was initially described as a Th2 cell-restricted receptor, but this has not been fully tested in vivo. The present study used ex vivo and in vivo approaches to examine the distribution and functional significance of CCR8 among CD4+ T cells. Populations of cytokine-secreting CD4+ T cells were generated in primed mice with Th1 or Th2 cell-mediated pulmonary granulomas, respectively elicited by i.v. challenge with either Mycobacteria bovis purified protein derivative- or Schistosoma mansoni egg Ag (SEA)-coated beads. Cytokine-producing CD4+ T cells were isolated from Ag-stimulated draining lymph node cultures by positive selection. Quantitative analysis of cytokine mRNA indicated enriched populations of IFN-gamma-, IL-4-, and IL-10-producing cells. Analysis of chemokine receptor mRNA indicated that IL-10+ cells selectively expressed CCR8 in the SEA bead-elicited type 2 response. The IL-10+CCR8+ populations were CD25+ and CD44+ but lacked enhanced Foxp3 expression. Adoptive transfer to naive recipients indicated that IL-10+ T cells alone could not transfer type 2 inflammation. Analysis of SEA bead-challenged CCR8-/- mice indicated significantly impaired IL-10 production as well as reductions in granuloma eosinophils. Adoptive transfer of CD4+CCR8+/+ T cells corrected cytokine and inflammation defects, but the granuloma eosinophil recruitment defect persisted when donor cells were depleted of IL-10+ cells. Accordingly, local IL-10 production correlated with CCR8 ligand (CCL1) expression and the appearance of CCR8+ cells in granulomatous lungs. Thus, IL-10-producing, CCR8+CD4+CD25+CD44+ T cells are generated during SEA challenge, which augment the Th2-mediated eosinophil-rich response to the parasite Ags.
Freeman
Christine M
CM
Department of Pathology, University of Michigan Medical School, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA.
Chiu
Bo-Chin
BC
Stolberg
Valerie R
VR
Hu
Jerry
J
Zeibecoglou
Kyriaki
K
Lukacs
Nicholas W
NW
Lira
Sergio A
SA
Kunkel
Steven L
SL
Chensue
Stephen W
SW
D019264:Adoptive Transfer; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002478:Cells, Cultured; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors; D015745:Granuloma, Foreign-Body / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000502:physiology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008863:Microspheres; D054401:Receptors, CCR8; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D012550:Schistosoma mansoni / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
D000947:Antigens, Helminth; C502258:Ccl1 protein, mouse; C489319:Ccr8 protein, mouse; D054402:Chemokine CCL1; D019742:Chemokines, CC; D016207:Cytokines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; D054401:Receptors, CCR8; D015375:Receptors, Interleukin-2; D016753:Interleukin-10