Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expansion.
The reason why CD4(+) T helper 17 (Th17) cells, despite their well-known pathogenic role in chronic inflammatory disorders, are very rare in the inflammatory sites remains unclear. We demonstrate that human Th17 cells exhibit low ability to proliferate and to produce the T cell growth factor interleukin-2 (IL-2), in response to combined CD3 and CD28 stimulation. This was due to the upregulated expression of IL-4-induced gene 1 (IL4I1) mRNA, a secreted L-phenylalanine oxidase, which associated with a decrease in CD3ζ chain expression and consequent abnormalities in the molecular pathway that allows IL-2 production and cell proliferation. High IL4I1 mRNA expression was detectable in Th17 cell precursors and was strictly dependent on Th17 cell master gene, the retinoid acid related orphan receptor (RORC). Th17 cells also exhibited RORC-dependent CD28 hyperexpression and the ability to produce IL-17A after CD28 stimulation without CD3 triggering. Our findings suggest that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms limiting their expansion.
Department of Internal Medicine and DENOTHE Center, University of Florence, 50134 Firenze, Italy.
Veronica
V
Santarlasci
Laura
L
Maggi
Manuela
M
Capone
Valentina
V
Querci
Luca
L
Beltrame
Duccio
D
Cavalieri
Elena
E
D'Aiuto
Rolando
R
Cimaz
Angela
A
Nebbioso
Francesco
F
Liotta
Raffaele
R
De Palma
Enrico
E
Maggi
Lorenzo
L
Cosmi
Sergio
S
Romagnani
Francesco
F
Annunziato
D001171:Arthritis, Juvenile / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation; D002648:Child; D015870:Gene Expression; D016762:Genes, fos; D016758:Genes, jun; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D050830:L-Amino Acid Oxidase / Q000235:genetics; D050778:NFATC Transcription Factors / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D018106:CD28 Antigens; D017252:CD3 Complex; C508717:IL17A protein, human; C508594:IL2 protein, human; D020381:Interleukin-17; D007376:Interleukin-2; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; C539900:RORC protein, human; C105158:IL4I1 protein, human; D050830:L-Amino Acid Oxidase