CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues.
The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4(+) T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4(+) T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6(-/-) mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3(+) cell frequency characterized CNS tissues from CCR6(-/-) compared with CCR6(+/+) mice during the disease effector phase. Transfer of CCR6(+/+) Treg to CCR6(-/-) mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3(+) cells and recovery of the cytokine balance in CCR6(-/-) mouse CNS. Competitive assays between CCR6(+/+) and CCR6(-/-) Treg adoptively transferred to CCR6(-/-) mice showed impaired ability of CCR6(-/-) Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4(+) Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.
Villares
Ricardo
R
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
Cadenas
Vanessa
V
Lozano
María
M
Almonacid
Luis
L
Zaballos
Angel
A
Martínez-A
Carlos
C
Varona
Rosa
R
D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002452:Cell Count; D002465:Cell Movement / Q000276:immunology*; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D054418:Chemokine CCL20 / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000032:analysis; D015870:Gene Expression / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D054399:Receptors, CCR6 / Q000502:physiology*; D012075:Remission, Spontaneous; D013116:Spinal Cord / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation
C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D054399:Receptors, CCR6; C445081:myelin oligodendrocyte glycoprotein (35-55)