Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease.
CD4(+)Foxp3(+) regulatory T cells (T reg) are essential for maintaining self-tolerance, but their functional mechanisms and sites of action in vivo are poorly defined. We examined the homing receptor expression and tissue distribution of T reg cells in the steady state and determined whether altering their distribution by removal of a single chemokine receptor impairs their ability to maintain tissue-specific peripheral tolerance. We found that T reg cells are distributed throughout all nonlymphoid tissues tested, and are particularly prevalent in the skin, where they express a unique CCR4(+)CD103(hi) phenotype. T reg cell expression of CCR4 and CD103 is induced by antigen-driven activation within subcutaneous lymph nodes, and accumulation of T reg cells in the skin and lung airways is impaired in the absence of CCR4 expression. Mice with a complete loss of CCR4 in the T reg cell compartment develop lymphocytic infiltration and severe inflammatory disease in the skin and lungs, accompanied by peripheral lymphadenopathy and increased differentiation of skin-tropic CD4(+)Foxp3(+) T cells. Thus, selectively altering T reg cell distribution in vivo leads to the development of tissue-specific inflammatory disease.
Sather
Blythe D
BD
Benaroya Research Institute, Seattle, WA 98101, USA.
Treuting
Piper
P
Perdue
Nikole
N
Miazgowicz
Mike
M
Fontenot
Jason D
JD
Rudensky
Alexander Y
AY
Campbell
Daniel J
DJ
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D039001:Integrin alpha Chains / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054398:Receptors, CCR4 / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; C515355:Ccr4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039001:Integrin alpha Chains; D054398:Receptors, CCR4; C091367:alpha E integrins