Revisión
Inmunología
Vol. 28 / Núm 1/ Enero-Marzo 2009: 32-45
The Th17 lineage:
Answers to some immunological questions
Coral González-García, Francisco M. Martín-Saavedra, Alicia Ballester, Sara Ballester
Unidad de Regulación Génica, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid.
EL LINAJE TH17: RESPUESTAS A ALGUNAS CUESTIONES INMUNOLÓGICAS
Recibido: 1 Diciembre 2008
Aceptado: 26 Enero 2009
RESUMEN ABSTRACT
En los últimos años se han estudiado exhaustivamente las funciones y In recent years the function and developmental pathway for the T
las rutas de desarrollo del subtipo de células T helper especializado en la pro- helper subset specialized in IL-17 production (Th17) have been exhausti-
ducción de IL-17 (Th17). Este linaje celular de células efectoras desempeña vely studied. This lineage of effector cells plays a decisive role in the immu-
un papel decisivo tanto en la respuesta inmune a agentes infecciosos, como ne response to infectious agents, as well as in immunopathologies. Simi-
en inmunopatologías. Al igual que para los subtipos Th1 y Th2, la definición lar to the Th1 and Th2 subsets, the Th17 definition is orchestrated by spe-
de Th17 está dirigida por citocinas y factores de transcripción específicos. La cific cytokines and transcription factors. A combination of TGF-β plus IL-
combinación de TGF-β e IL-6, y los factores de transcripción RORγt, RORα 6, and the transcription factors RORγt, RORα and Stat3 are essential for
y Stat3 son esenciales para comprometer el subtipo Th17. IL-23 juega un papel Th17 commitment. IL-23 plays a key role in the stabilization of the phe-
clave en la estabilización del fenotipo y de la actividad patogénica de células notype and in the promotion of the pathogenic activity of IL-17-producer
productoras de IL-17. La citocina IL-21 producida por células Th17 participa cells. The IL-21 cytokine produced by Th17 cells participates in a feedback
en un mecanismo de retroalimentación para favorecer el desarrollo de célu- mechanism to favour this phenotype, while IL-27, IL-4, IFN-γ, IL-25 and
las productoras de IL-17, mientras que las citocinas IL-27, IL-4, IFN-γ, IL-25 IL-2 cytokines limit the Th17 response. CD4+CD25+Foxp3+ regulator cells
e IL-2 limitan el fenotipo Th17. Las células T reguladoras CD4+CD25+Foxp3+ (Treg) follow a development pathway divergent to Th17 establishment,
(Treg) siguen una ruta de desarrollo divergente al establecimiento de las célu- although both alternatives are governed by TGF-β that directs the fate
las IL-17, aunque ambas alternativas son gobernadas por TGF-β, el cual diri- of naïve CD4+ cells to each of these mutually exclusive T cell subsets depen-
ge el destino de células CD4+ naïve hacia uno u otro de estos subtipos celu- ding on the presence of IL-6. Furthermore, recent data indicate that pre-
lares mutuamente excluyentes dependiendo de la presencia de IL-6. Ade- established Treg cells can switch its genetic program to become IL-17-pro-
más, datos recientes indican que células Treg ya establecidas pueden modi- ducer cells. In this review we summarize and discuss the current availa-
ficar su programa genético para convertirse en células Th17. En esta revisión ble data about the biology of Th17 cells.
se resumen y analizan los datos disponibles actualmente acerca de la biolo-
gía de las células Th17. KEY WORDS: Th17 / TGF-β / IL-6 / IL-23 / RORγt.
PALABRAS CLAVE: Th17 / TGF-β / IL-6 / IL-23 / RORγt.
32
, INMUNOLOGÍA CORAL GONZÁLEZ-GARCÍA, FRANCISCO M. MARTÍN-SAAVEDRA, ALICIA BALLESTER AND SARA BALLESTER
THE IL-17 FAMILY TRAF6 was shown to be involved in the activation of NFκB
Since Mossman et al. proposed the model wherein CD4+ by IL-17(17). On the other hand, IL-17 can increase expression
T helper cells were classified in Th1 and Th2 subtypes with of some of its target genes through mRNA stabilization(18).
different functions in immune responses according to the IL-17B and IL-17C are members of the family whose
profile of cytokines produced(1), the Th1/Th2 paradigm cellular sources are unknown yet, and whose biology seems
provided a valuable tool to understand the interplay of unrelated to IL-17A. In this review, we will refer to IL-17A
innate and adaptive immunity and CD4+ T cell function. as IL-17.
However, some discrepancies have arisen related to results
that did not fit in the Th1/Th2 hypothesis. During the
past years new studies have identified a distinct subset of CLUES TO THE IDENTIFICATION OF A NEW T
CD4+ T cells that secrete IL-17 and the closely related cytokine HELPER CELL LINEAGE PRODUCING IL-17
IL-17F as well as other inflammatory cytokines such as IL- The first suggestion of a new T helper subset, distinct
6 and IL-22(2,3). from Th1 and Th2, was provided by the finding of T CD4+
Murine IL-17 was described as CTLA-8(4), and a 63% cells producing high levels of IL-17 without expression of
homologous human cytokine was soon found(5). Currently, IFN-γ or IL-4, the respective prototype cytokines produced
the IL-17 cytokines include a family of six members (IL-17A- by Th1 and Th2(19). Other important clues were supplied
F), with at least two of them having potent proinflammatory by studies on animal models of autoimmunity. Pathologies
properties: IL-17A or CTLA-8 (the founder member of the such as experimental autoimmune encephalomyelitis (EAE)
family also named IL-17), and IL17-F. Both are produced and collagen-induced arthritis (CIA), or mouse models
by the recently described Th17 cell subset, are localized at for human multiple sclerosis (MS) and rheumatoid arthritis
the same chromosomal locus (1A4), share a 55% of homology (RA), have been traditionally considered as Th1-mediated
at the protein level, and seem to have similar functions. IL- diseases. However, over the years, a number of experimental
17A and IL-17F work mostly as homodimers, but IL-17A/F results showed inconsistencies with the Th1/Th2 hypothesis.
heterodimers have been recently described in several For example, depletion of the Th1 cytokine IFN-γ, its
independent reports(6-8), suggesting a role in inflammatory receptor IFN-γR, or the IL-12 receptor (IL-12Rβ2), the master
response regulation for such IL-17 complexes. IL-17D and inductor of the Th1 phenotype, increased the susceptibility
IL-17E (alternative names: IL-27 and IL-25) are the two to EAE(20-26).
members of the IL-17 family with lowest homology (16% With the discovery of IL-23 as an heterodimeric cytokine
at protein level) to IL-17A. None of them is produced by sharing its p40 subunit with IL-12(27), the relative contribution
Th17 cells, and both of them, as discussed later, exert a of IL-12 and IL-23 to chronic inflammation could be analyzed.
negative control on the Th17 subset development. The IL-12 heterodimer is composed by the p40 and p35
IL-17 receptors are a family of five members of membrane subunits, while IL-23 comprises p40 and a different p19
proteins, IL-17RA-F(9). Except for IL-17RA, each of these protein. By using mice lacking IL-23 (p19-/-), IL-12 (p35-/-) or
receptors has alternative splicing variants, and, for IL-17RB both cytokines (p40-/-), it could be demonstrated that IL-23,
and IL-17RC, result in secreted soluble proteins which could and not IL-12, is the critical cytokine for autoimmune
serve to antagonize their ligands(10). IL-17A and IL-17F bind inflammation of the central nervous system (CNS) during
to IL-17RA, although IL-17A binds with much higher EAE(28). This study was followed by many other showing
affinity(11), which correlates with its greater potency in the role of IL-23 in inflammation(29-31). In parallel with these
functions like induction of chemokine expression(8). In findings, it was reported that IL-17-producer cells could be
addition to IL-17RA, IL-17F can also bind to IL-17RC. By generated independently of the cytokines and transcription
signalling through IL-17RA, which is ubiquitously expressed, factors required for Th1 or Th2 differentiation. The development
IL-17 can induce the production of different kinds of proteins, of Th17 from naïve cells was potently inhibited by IFN-γ and
many of them related to inflammation, including chemokines IL-4, whereas memory Th17 cells were resistant to suppression
(CXCL-1, CXCL-2, CXCL-8-10, CCL-2, CCL-20), cytokines by Th1 or Th2 cytokines, indicating that these cells had a
(IL-6, TNFα, G-CSF, GM-CSF), proteins of the acute phase permanent commitment. All these data together indicated
response, tissue remodelling factors (MMP1, MMP3, MMP9, that a T helper lineage distinct from Th1 and Th2 can
MMP13, TIMP2), and anti-microbial products (β-defensins, differentiate from naïve CD4+ cells to produce IL-17(2, 3).
mucins, calgranulins)(12). The signal transduction of IL-17 is In 2006, three independent reports provided the basis
mainly mediated by NFκB and C/EBP transcription factors, for understanding the process of Th17 cell promotion(32-34).
with the involvement of MAP kinase pathways(13-16). Moreover, All of them found that transforming growth factor β (TGF-
33
Inmunología
Vol. 28 / Núm 1/ Enero-Marzo 2009: 32-45
The Th17 lineage:
Answers to some immunological questions
Coral González-García, Francisco M. Martín-Saavedra, Alicia Ballester, Sara Ballester
Unidad de Regulación Génica, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid.
EL LINAJE TH17: RESPUESTAS A ALGUNAS CUESTIONES INMUNOLÓGICAS
Recibido: 1 Diciembre 2008
Aceptado: 26 Enero 2009
RESUMEN ABSTRACT
En los últimos años se han estudiado exhaustivamente las funciones y In recent years the function and developmental pathway for the T
las rutas de desarrollo del subtipo de células T helper especializado en la pro- helper subset specialized in IL-17 production (Th17) have been exhausti-
ducción de IL-17 (Th17). Este linaje celular de células efectoras desempeña vely studied. This lineage of effector cells plays a decisive role in the immu-
un papel decisivo tanto en la respuesta inmune a agentes infecciosos, como ne response to infectious agents, as well as in immunopathologies. Simi-
en inmunopatologías. Al igual que para los subtipos Th1 y Th2, la definición lar to the Th1 and Th2 subsets, the Th17 definition is orchestrated by spe-
de Th17 está dirigida por citocinas y factores de transcripción específicos. La cific cytokines and transcription factors. A combination of TGF-β plus IL-
combinación de TGF-β e IL-6, y los factores de transcripción RORγt, RORα 6, and the transcription factors RORγt, RORα and Stat3 are essential for
y Stat3 son esenciales para comprometer el subtipo Th17. IL-23 juega un papel Th17 commitment. IL-23 plays a key role in the stabilization of the phe-
clave en la estabilización del fenotipo y de la actividad patogénica de células notype and in the promotion of the pathogenic activity of IL-17-producer
productoras de IL-17. La citocina IL-21 producida por células Th17 participa cells. The IL-21 cytokine produced by Th17 cells participates in a feedback
en un mecanismo de retroalimentación para favorecer el desarrollo de célu- mechanism to favour this phenotype, while IL-27, IL-4, IFN-γ, IL-25 and
las productoras de IL-17, mientras que las citocinas IL-27, IL-4, IFN-γ, IL-25 IL-2 cytokines limit the Th17 response. CD4+CD25+Foxp3+ regulator cells
e IL-2 limitan el fenotipo Th17. Las células T reguladoras CD4+CD25+Foxp3+ (Treg) follow a development pathway divergent to Th17 establishment,
(Treg) siguen una ruta de desarrollo divergente al establecimiento de las célu- although both alternatives are governed by TGF-β that directs the fate
las IL-17, aunque ambas alternativas son gobernadas por TGF-β, el cual diri- of naïve CD4+ cells to each of these mutually exclusive T cell subsets depen-
ge el destino de células CD4+ naïve hacia uno u otro de estos subtipos celu- ding on the presence of IL-6. Furthermore, recent data indicate that pre-
lares mutuamente excluyentes dependiendo de la presencia de IL-6. Ade- established Treg cells can switch its genetic program to become IL-17-pro-
más, datos recientes indican que células Treg ya establecidas pueden modi- ducer cells. In this review we summarize and discuss the current availa-
ficar su programa genético para convertirse en células Th17. En esta revisión ble data about the biology of Th17 cells.
se resumen y analizan los datos disponibles actualmente acerca de la biolo-
gía de las células Th17. KEY WORDS: Th17 / TGF-β / IL-6 / IL-23 / RORγt.
PALABRAS CLAVE: Th17 / TGF-β / IL-6 / IL-23 / RORγt.
32
, INMUNOLOGÍA CORAL GONZÁLEZ-GARCÍA, FRANCISCO M. MARTÍN-SAAVEDRA, ALICIA BALLESTER AND SARA BALLESTER
THE IL-17 FAMILY TRAF6 was shown to be involved in the activation of NFκB
Since Mossman et al. proposed the model wherein CD4+ by IL-17(17). On the other hand, IL-17 can increase expression
T helper cells were classified in Th1 and Th2 subtypes with of some of its target genes through mRNA stabilization(18).
different functions in immune responses according to the IL-17B and IL-17C are members of the family whose
profile of cytokines produced(1), the Th1/Th2 paradigm cellular sources are unknown yet, and whose biology seems
provided a valuable tool to understand the interplay of unrelated to IL-17A. In this review, we will refer to IL-17A
innate and adaptive immunity and CD4+ T cell function. as IL-17.
However, some discrepancies have arisen related to results
that did not fit in the Th1/Th2 hypothesis. During the
past years new studies have identified a distinct subset of CLUES TO THE IDENTIFICATION OF A NEW T
CD4+ T cells that secrete IL-17 and the closely related cytokine HELPER CELL LINEAGE PRODUCING IL-17
IL-17F as well as other inflammatory cytokines such as IL- The first suggestion of a new T helper subset, distinct
6 and IL-22(2,3). from Th1 and Th2, was provided by the finding of T CD4+
Murine IL-17 was described as CTLA-8(4), and a 63% cells producing high levels of IL-17 without expression of
homologous human cytokine was soon found(5). Currently, IFN-γ or IL-4, the respective prototype cytokines produced
the IL-17 cytokines include a family of six members (IL-17A- by Th1 and Th2(19). Other important clues were supplied
F), with at least two of them having potent proinflammatory by studies on animal models of autoimmunity. Pathologies
properties: IL-17A or CTLA-8 (the founder member of the such as experimental autoimmune encephalomyelitis (EAE)
family also named IL-17), and IL17-F. Both are produced and collagen-induced arthritis (CIA), or mouse models
by the recently described Th17 cell subset, are localized at for human multiple sclerosis (MS) and rheumatoid arthritis
the same chromosomal locus (1A4), share a 55% of homology (RA), have been traditionally considered as Th1-mediated
at the protein level, and seem to have similar functions. IL- diseases. However, over the years, a number of experimental
17A and IL-17F work mostly as homodimers, but IL-17A/F results showed inconsistencies with the Th1/Th2 hypothesis.
heterodimers have been recently described in several For example, depletion of the Th1 cytokine IFN-γ, its
independent reports(6-8), suggesting a role in inflammatory receptor IFN-γR, or the IL-12 receptor (IL-12Rβ2), the master
response regulation for such IL-17 complexes. IL-17D and inductor of the Th1 phenotype, increased the susceptibility
IL-17E (alternative names: IL-27 and IL-25) are the two to EAE(20-26).
members of the IL-17 family with lowest homology (16% With the discovery of IL-23 as an heterodimeric cytokine
at protein level) to IL-17A. None of them is produced by sharing its p40 subunit with IL-12(27), the relative contribution
Th17 cells, and both of them, as discussed later, exert a of IL-12 and IL-23 to chronic inflammation could be analyzed.
negative control on the Th17 subset development. The IL-12 heterodimer is composed by the p40 and p35
IL-17 receptors are a family of five members of membrane subunits, while IL-23 comprises p40 and a different p19
proteins, IL-17RA-F(9). Except for IL-17RA, each of these protein. By using mice lacking IL-23 (p19-/-), IL-12 (p35-/-) or
receptors has alternative splicing variants, and, for IL-17RB both cytokines (p40-/-), it could be demonstrated that IL-23,
and IL-17RC, result in secreted soluble proteins which could and not IL-12, is the critical cytokine for autoimmune
serve to antagonize their ligands(10). IL-17A and IL-17F bind inflammation of the central nervous system (CNS) during
to IL-17RA, although IL-17A binds with much higher EAE(28). This study was followed by many other showing
affinity(11), which correlates with its greater potency in the role of IL-23 in inflammation(29-31). In parallel with these
functions like induction of chemokine expression(8). In findings, it was reported that IL-17-producer cells could be
addition to IL-17RA, IL-17F can also bind to IL-17RC. By generated independently of the cytokines and transcription
signalling through IL-17RA, which is ubiquitously expressed, factors required for Th1 or Th2 differentiation. The development
IL-17 can induce the production of different kinds of proteins, of Th17 from naïve cells was potently inhibited by IFN-γ and
many of them related to inflammation, including chemokines IL-4, whereas memory Th17 cells were resistant to suppression
(CXCL-1, CXCL-2, CXCL-8-10, CCL-2, CCL-20), cytokines by Th1 or Th2 cytokines, indicating that these cells had a
(IL-6, TNFα, G-CSF, GM-CSF), proteins of the acute phase permanent commitment. All these data together indicated
response, tissue remodelling factors (MMP1, MMP3, MMP9, that a T helper lineage distinct from Th1 and Th2 can
MMP13, TIMP2), and anti-microbial products (β-defensins, differentiate from naïve CD4+ cells to produce IL-17(2, 3).
mucins, calgranulins)(12). The signal transduction of IL-17 is In 2006, three independent reports provided the basis
mainly mediated by NFκB and C/EBP transcription factors, for understanding the process of Th17 cell promotion(32-34).
with the involvement of MAP kinase pathways(13-16). Moreover, All of them found that transforming growth factor β (TGF-
33
