Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-beta.
Invariant NKT (iNKT) cells were shown to prevent the onset of experimental autoimmune encephalomyelitis in mice following administration of their specific TCR agonist alpha-galactosylceramide. We found that this protection was associated with the emergence of a Foxp3(+) iNKT cell population in cervical lymph nodes. We demonstrate that the differentiation of these cells is critically dependent on TGF-beta in both mice and humans. Moreover, in vivo generation of Foxp3(+) iNKT cells was observed in the TGF-beta-rich environment of the murine gut. Foxp3(+) iNKT cells displayed a phenotype similar to that of Foxp3(+) regulatory T cells, and they suppress through a contact-dependent, glucocorticoid-induced TNFR-mediated mechanism. Nevertheless, Foxp3(+) iNKT cells retain distinctive NKT cell characteristics, such as promyelocytic leukemia zinc finger protein expression and preferential homing to the liver following adoptive transfer, where they stably maintained Foxp3 expression. Our data thus unveil an unexpected capacity of iNKT cells to acquire regulatory functions that may contribute to the establishment of immunological tolerance.
Monteiro
Marta
M
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Almeida
Catarina F
CF
Caridade
Marta
M
Ribot
Julie C
JC
Duarte
Joana
J
Agua-Doce
Ana
A
Wollenberg
Ivonne
I
Silva-Santos
Bruno
B
Graca
Luis
L
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005699:Galactosylceramides; D016212:Transforming Growth Factor beta; C493154:alpha-galactosylceramide