IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner.
CD4(+) helper T cells can differentiate into several possible fates including: Th1, Th2, T regulatory, and Th17 cells. Although, cytokine production by non-T cells is an important factor in helper T cell differentiation, a characteristic feature of both Th1 and Th2 lineages is their ability to secrete cytokines that promote their respective differentiation. However, cytokines produced by T cells that help to sustain Th17 cells have not yet been identified. Here we show that IL-21 is a product of Th17 cells, which is induced in a Stat3-dependent manner. Additionally, Stat3 can directly bind the Il21 promoter. IL-21 also induces IL-17 production and expression of the transcription factor, RORgammat. Furthermore, generation of Th17 cells in the conventional manner is attenuated by blocking IL-21. IL-21 is known to activate Stat3 and its ability to induce Th17 differentiation is abrogated in the absence of Stat3. These data argue that IL-21 serves as an autocrine factor secreted by Th17 cells that promotes or sustains Th17 lineage commitment.
Wei
Lai
L
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. weil2@mail.nih.gov
Laurence
Arian
A
Elias
Kevin M
KM
O'Shea
John J
JJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000096:biosynthesis*; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism*; D000098546:Interleukin-21
D016207:Cytokines; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21