Transforming growth factor-beta induces development of the T(H)17 lineage.
A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (T(H)17) lineage, was recently described based on developmental and functional features distinct from those of classical T(H)1 and T(H)2 lineages. Like T(H)1 and T(H)2, T(H)17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant T(H)17 responses have been implicated in a growing list of autoimmune disorders. T(H)17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rbeta1, that pairs with unique, inducible components, IL-23R and IL-12Rbeta2, to confer receptor responsiveness. Here we identify transforming growth factor-beta (TGF-beta) as a cytokine critical for commitment to T(H)17 development. TGF-beta acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-beta on naive T cells is antagonized by interferon-gamma and IL-4, thus providing a mechanism for divergence of the T(H)1, T(H)2 and T(H)17 lineages.
Mangan
Paul R
PR
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-2170, USA.
Harrington
Laurie E
LE
O'Quinn
Darrell B
DB
Helms
Whitney S
WS
Bullard
Daniel C
DC
Elson
Charles O
CO
Hatton
Robin D
RD
Wahl
Sharon M
SM
Schoeb
Trenton R
TR
Weaver
Casey T
CT
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D018123:Receptors, Interleukin / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma