The immune paradox of sarcoidosis and regulatory T cells.
Sarcoidosis is characterized by extensive local inflammation (granuloma, cytokine secretion) associated with anergy (poor response to antigens in vitro and in vivo). We postulated that this paradoxical situation would correspond to a disequilibrium between effector and regulatory T lymphocytes (T reg cells). We show that CD4+CD25(bright)FoxP3+ cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of patients with active disease. These cells exhibited powerful antiproliferative activity, yet did not completely inhibit TNF-alpha production. Sarcoidosis is therefore associated with a global T reg cell subset amplification whose activity would be insufficient to control local inflammation. At the same time, peripheral T reg cells exert powerful antiproliferative activity that may account for the state of anergy. Altogether, these findings advance our conceptual understanding of immune regulation in a way that resolves the immune paradox of sarcoidosis and permit us to envisage a profound clinical impact of T reg cell manipulation on immunity.
Miyara
Makoto
M
Institut National de la Santé et de la Recherche Médicale (INSERM) U543, Immunologie A, 75013 Paris, France.
Amoura
Zahir
Z
Parizot
Christophe
C
Badoual
Cécile
C
Dorgham
Karim
K
Trad
Salim
S
Kambouchner
Marianne
M
Valeyre
Dominique
D
Chapelon-Abric
Catherine
C
Debré
Patrice
P
Piette
Jean-Charles
JC
Gorochov
Guy
G
D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006099:Granuloma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D017565:Sarcoidosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C515187:CXCR3 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma