IL-21 is a member of the common γ-chain signaling family of cytokines. Analyses of the behavior of immune cells in response to IL-21 in vitro and studies of mice deficient in IL-21 or its receptor indicate that IL-21 has a role in lymphocyte activation, proliferation, differentiation, and survival. IL-21–producing CD4+ Th cells constitute a broad array of helper subtypes including T follicular helper cells and Th17 cells. Both autocrine and paracrine utilization of IL-21 contributes to the overall signal transduction pathways of the Ag receptor to influence the growth and survival of lymphocytes. The redundancy that IL-21 exhibits in lymphoid organs during immune responses is in stark contrast to the evidence that pharmacological neutralization of this cytokine can halt inflammation in nonlymphoid organs where IL-21 becomes the dominant voice.

Interleukin-21 is an IL-2 family cytokine produced by activated T cells to regulate immune responses (1). This pleiotropic cytokine functions in both an autocrine and paracrine manner (2) via a heterodimeric receptor consisting of the specific IL-21R and the common γ-chain receptor, with the latter also being shared by IL-2, IL-4, IL-7, and IL-15. Other cells such as NKT cells and γδ T cells have also been reported to produce IL-21 (1, 3). Importantly, IL-21 is pivotal to Th cell differentiation (2, 48) as well as driving the expansion and promoting the survival of both CD4+ and CD8+ T cells (1, 9, 10). CD8+ T cells are an important target of the actions of IL-21. Transgenic overexpression of murine IL-21 revealed predominant expansion of memory phenotype CD8+ T cells (11), and numerous studies have demonstrated that CTL functions are also dependent on IL-21 (1, 12). In addition to T cells, B cells rely on IL-21 for survival and differentiation, supporting the production of Ab-forming cells with class-switched Ig (13). Although IL-21 has important lymphocyte-intrinsic effects, IL-21R is widely expressed on cells of both the adaptive and innate immune system as well as nonimmune cells (14, 15).

IL-21 is strongly linked with inflammation and autoimmunity. We previously reported that increased levels of IL-21 mRNA and IL-21–dependent increases in T cell expansion formed a basis for autoimmunity in the NOD mouse (9). Elevated amounts of IL-21 have subsequently been reported in many autoimmune diseases, including type 1 diabetes (T1D) (9, 14, 16), systemic lupus erythematosus (SLE) (17, 18), and inflammatory bowel diseases (IBDs) (19, 20), where IL-21 protein and mRNA levels were correlated with disease severity. These findings are likely to reflect the fact that activated T cells, which are enriched during inflammation, produce IL-21. IL-21 as a product of acute inflammation is highlighted by the observation that the amounts of IL-21 in peripheral blood and mucosa of IBD patients in remission are not significantly different from those of healthy individuals (19, 21). The contributing role of IL-21 to autoimmunity has been confirmed in several studies showing that mice were protected from autoimmune diseases including T1D (2225), lupus (26), colitis (20), and rheumatoid arthritis (RA) (27) when IL-21 signaling is blocked, or in mice genetically deficient in IL-21 or IL-21R.

IL-21 drives inflammation by promoting the expansion and survival of lymphocytes. Studies also show that IL-21 can inhibit the induction of Foxp3+ regulatory T (Treg) cells (2, 4). However, whether IL-21 acts directly upon Treg cells or makes effector cells less “suppressible” remains controversial. Apart from priming the immune system, IL-21 has also been reported to have inhibitory effects via the induction of subsets of IL-10–producing Treg and B cells. The IL-12 cytokine family member IL-27, as well as IL-6, induces IL-10–producing Foxp3 regulatory type 1 T cells in an IL-21–dependent manner; these Treg cells coproduce IL-21 (28, 29).

Whereas IL-21 can be produced by many CD4+ T cells, specific helper subsets have been reported to secrete IL-21 at the highest levels, namely T follicular helper (Tfh) cells (30), Th17 cells (2, 4, 5, 30), and recently described CCR9-bearing Th cells in mucosal tissues (10). In this review we discuss these Th cell subsets and their roles in immunity and autoimmunity.

Tfh cells are a specialized subset of CD4+ T cells that provide help to B cells for the generation of Ab-forming cells that produce affinity-matured Ab (31). Tfh cells, as their name suggests, are localized within B cell follicles. Tfh cells migrate into specialized structures formed inside B cell follicles known as the germinal center (GC) through high surface expression CXCR5 and downregulation of CCR7 that guides Tfh cells away from the T cell zone where the ligands for CCR7 (CCL19 and CCL21) are expressed and toward the ligand for CXCR5 (CXCL13), a chemoattractant produced by follicular dendritic cells at the central locus of the GC (32, 33). Tfh cells are typically characterized by high expression of both CXCR5 and the coinhibitory molecule programmed cell death 1 (PD-1). Tfh cells are selectively derived from precursors with high affinity to Ag (34), consistent with the observation that the magnitude of Tfh cell generation is influenced by costimulation of the TCR (6) and by Ag dose delivered at initial contact with dendritic cells (35). However, Tfh cells reciprocally depend on B cells; whereas the initial differentiation of Tfh cells can be mediated by APCs, such as dendritic cells, in the absence of B cells (35), the maintenance and function of this subset during GC reactions is B cell–dependent (36).

In addition to CXCR5 and PD-1, Tfh cells are characterized by high expression of cell surface molecules and cytokines that are important for the interaction with B cells (i.e., CD40L, ICOS, IL-4, and IL-21) (31). Tfh cells have been reported to produce the highest amounts of IL-21, a cytokine that is also important for their differentiation and survival (2, 6, 8, 37). IL-21 has been well established to support the generation and differentiation of B cells (17, 38). For Tfh cell generation or differentiation, IL-6 exhibits redundancy with IL-21 (39, 40) and furthermore promotes IL-21 production during T cell activation (5, 8). However, to what relative extent both cytokines are used by Tfh cells during an immune response in unmanipulated mice or in humans remains unknown. The extent to which responsiveness to IL-21 is required for Tfh cells during the generation of Ab responses remains controversial. This may be due to the influence of costimulation by IL-21 being dependent on the form of Ag delivered, variations of whether a functional readout for Tfh cells (affinity-matured Ab) was used in studies, which has been confounded by a phenotypic characterization of Tfh cells that is based on surface markers that are commonly expressed on activated CD4+ T cells. A recent study has highlighted this issue, demonstrating that despite being phenotypically “Tfh-like,” IL-21R–deficient Tfh cells were functionally devoid of B helper activity and that IL-21 signaling was intrinsically required in CD4+ T cells to generate fully functional Tfh cells for the generation of long-term humoral immunity to viruses (41). Whether IL-21 influences Tfh cells in a quantitative or qualitative manner remains an important unanswered question.

The transcription factor Bcl-6 is necessary for Tfh cell generation (42). IL-21 influences the expression of Bcl-6, Prdm1 (encoding Blimp-1) (17, 43), and c-Maf (44), transcription factors that are central to Tfh development. Expression of IL-21 and c-Maf are mutually dependent, as c-Maf is reported to transactivate IL-21, and accordingly IL-21 expression is deficient in c-Maf−/− mice (29, 44). Consistent with the important role of STAT3 signaling cytokines such as IL-21 and IL-6 for Tfh cells, STAT3 deficiency compromises the generation of human Tfh cells (45). IL-27, in turn, induces IL-21 production by T cells in a STAT3-dependent manner and is required for Tfh cell function as well as GC responses (46). Whereas IL-27 is necessary for optimal Tfh cell generation, it is not sufficient to drive this program. In addition to inducing IL-21, IL-27 induces IL-21R expression (29) and enhances expression of pivotal Tfh molecules, including ICOS and c-Maf, and promotes survival of Tfh cells (29, 46). In contrast to Th17 cells, TGF-β is not required for Tfh cell differentiation (8). In fact, exogenous TGF-β has been shown to inhibit IL-21 secretion induced by either IL-6 or IL-21 (47).

Although Tfh cells, at the population level, are characterized by high production of IL-21, expression of this cytokine is not essential for their effector functions at the individual cell level. After immunization, only a fraction (30–40%) of Tfh cells secreted IL-21 throughout different phases of the response (30). Indeed, IL-21 Tfh cells were reported to function just as well as IL-21+ Tfh cells, including localization to the B cell follicles, expression of CXCR5 and PD-1, providing help to B cells, and inducing class switching (30). Tfh cells are reported to secrete effector cytokines other than IL-21, including IL-4 and IFN-γ (48). However, the extent to which Tfh cells secrete other cytokines has been the subject of controversy, which could reflect experimental variations in their induction and differentiation (6, 8, 44, 49).

IL-17–producing CD4+ T cells feature prominently in inflamed tissues and have been implicated in both protective and pathogenic functions in the immune system. In addition to their hallmark cytokine IL-17 (IL-17A), Th17 cells also produce IL-17F, IL-21, and IL-22 (50). In mice, TGF-β is required for the induction of both proinflammatory Th17 and peripherally induced Treg cells (50). TGF-β and IL-6 coordinately induce Th17 cell differentiation, whereby IL-6 is a switch factor that promotes Th17 cell development while inhibiting the induction of Treg cells (50). Initially, IL-23 was identified as the differentiation factor for Th17 cells from naive T cells, but it was subsequently demonstrated to be a cytokine critically required for the stabilization of existing Th17 cells (51, 52) and to enhance the pathogenicity of Th17 cells (53, 54).

IL-21 is produced by Th17 cells, and the primary roles for IL-21 in mouse Th17 cell development are expansion of existing Th17 cells (52) and antagonizing induction of Treg cells in the periphery (2, 4). However, Th17 cells can develop in the absence of IL-21/IL-21R signaling (55, 56). Similar to Tfh cells, IL-6 induces the production of IL-21 in Th17 cells, and in turn IL-21 induces expression of IL-23R on Th17 cells, thus further stabilizing the phenotype (5). Indeed, generation of Th17 cells is reported to be impaired in the absence of IL-21 signaling (2, 4, 5). IL-21−/− T cells display suboptimal Th17 cell generation in vitro, demonstrating the ability of IL-21 to act in an autocrine manner for Th17 cell differentiation.

Transcription factors cruicial for Th17 development include retinoic acid–related orphan receptor (ROR)γt, STAT3, and IFN regulatory factor 4. RORγt, encoded by Rorc, has been considered the master regulator of Th17 cells, whereas IRF4 is essential for IL-21 signaling (5759). STAT3 is required for signaling of several cytokines critical to Th17 cell development and function, including IL-6, IL-21, IL-23, and IL-22 (2, 5, 60). Defective Th17 responses have been reported in mice deficient in any of these transcription factors. In line with these observations, immunodeficient patients with dominant-negative mutations in STAT3 are profoundly deficient in circulating Th17 cells (6163).

Recently, we described a subset of IL-21–producing Th cells that expressed the gut-homing receptor CCR9 (10). CCR9+ Th cells from the pancreas and pancreatic draining lymph node of NOD mice that spontaneously develop T1D did not produce cytokines associated with Th1, Th2, or Th17 or express Gata3 or Rorc mRNA. However, they did express Tfh cell–associated molecules, including ICOS, Bcl-6, and c-Maf, and supported production of Abs by B cells. Analogous to Tfh cells, CCR9+ Th cells are expanded in the peripheral blood of patients with Sjörgren’s syndrome and in autoimmune mice. Intriguingly, these Tfh-like cells did not express CXCR5 (10). However, CCR9+ Th cells that coexpressed CXCR5 (CCR9+ Tfh cells) were also identified in NOD mice (10). Interestingly, CCR9+ Tfh cells in the Peyer’s patches (PP) upregulated prototypical Th17 molecules, including Il17a, Il17f, Rorc, Il22, Il23r, and Ccr6 (C. King, unpublished observations). It is plausible that these cells represent Tfh cells activated in the tissues associated with mucosal inflammation, thereby acquiring CCR9 expression (Fig. 1). Indeed, effector T cells have been demonstrated to convert to a Tfh cell–like phenotype in the PP to induce IgA production (64), and this is discussed in more detail below.

FIGURE 1.

Transitioning between sequential Th programs. Plasticity of IL-21–producing Th cells in gastric mucosal tissues and accessory organs is shown. Dotted lines indicate potential for conversion to other Th cells in different inflamed tissues and microenvironments. The solid black arrows represent conversion from one Th program to another in the gut microenvironment.

FIGURE 1.

Transitioning between sequential Th programs. Plasticity of IL-21–producing Th cells in gastric mucosal tissues and accessory organs is shown. Dotted lines indicate potential for conversion to other Th cells in different inflamed tissues and microenvironments. The solid black arrows represent conversion from one Th program to another in the gut microenvironment.

Close modal

The molecular pathways that govern Tfh and Th17 cell differentiation substantially overlap, and functional similarities exist between them (49, 65, 66). The differentiation of both of these Th subsets can be induced by IL-6 and IL-21, and they rely on STAT3 signaling for their development (2, 5, 45, 61). Expression of c-Maf is also common (44), and costimulation via ICOS/ICOSL interactions is critically required for the development of both helper subsets (6, 44, 67). Furthermore, in autoimmune BDX2 mice, IL-17 from CD4+ T cells promotes the formation of GC and is pivotal to the unrestrained production of autoantibodies via direct effects on B cells (49).

One of the initial hints that Th17 cells retained plasticity came from the observation that Th17 cells converted to an IFN-γ–producing phenotype after adoptive transfer, even when IL-17–producing cells were highly purified using specific tetramers (68, 69). By using more sophisticated tools and methods for tracking T cells in vivo, it became apparent that endogenous Th17 cells could transform into Th1, Tfh, or Treg cells or retain a Th17 phenotype, depending on the nature of the immune response and the microenvironment of the target tissue (64, 70, 71). Using fate-reporter mice, in which cells that produced IL-17 at any point during their development permanently switched on enhanced yellow fluorescent protein (eYFP) expression, Th17 cells could be seen to transition from IL-17+IFN-γ to IL-17+IFN-γ+ and again to IL-17IFN-γ+ expression (71). This study also confirmed that the switch of Th17 cells to IFN-γ production was necessary for the development of experimental autoimmune encephalomyelitis (EAE) and showed that this process was facilitated by IL-23. Such fate-mapping experiments validated the previous conclusion drawn that conversion of adoptively transferred Th17 cells to IFN-γ production was a requirement for the development of T1D in NOD mice (69).

Suppressive Th17 cells that produce IL-10 were discovered in the small intestine using IL-17A-eGFP reporter mice (70), similar to those identified in in vitro experiments (53). Under noninflammatory conditions, CCR6-expressing Th17 cells preferentially home to the intestinal mucosa where the expression of its ligand CCL20 is enriched. At this site, Th17 cells could be converted either to a regulatory phenotype (70) or a Tfh cell–like phenotype in the PP (64). A follow-up study using fate-reporter mice showed that Th17 cells downregulated Il17a and Rorc and transitioned into Tfh cells in the PP. In fact, Tfh cells in the PP that help B cells make Ag-specific IgA were absent in Th17-deficient mice (64). Under steady-state conditions, almost half of the Tfh cells in the PP of mice were former Th17 cells (eYFP+), and of these ex-Th17 cells, up to 20% switched to a Tfh cell phenotype expressing CXCR5, PD-1, Il21, and Bcl6 (64). Upon immunization with cholera toxin, the proportion of eYFP+ cells that converted to a Tfh cell phenotype increased and was associated with strong Ag-specific IgA production. The mechanism of the transition from Th17 to Tfh cells in the PP remains unclear.

Tfh cells can initiate secondary programs as functional Th1/Th2/Th17/Treg cells depending on local environmental cues (72). Upon adoptive transfer, IL-21+ Tfh cells from IL-21 reporter mice had the potential to differentiate into conventional effector cells (30). Tfh cells have been reported to acquire effector functions associated with other Th subsets, producing IL-17 (44, 49), IL-4 (48), and IFN-γ in some studies, but not IL-17 (6, 8) or IL-4 (48) in others. Foxp3+ Treg cells have been demonstrated to transform into Tfh cells in the PP upon adoptive transfer (73). Recent studies have proposed that Tfh cells are controlled by Foxp3+ follicular Treg cells, which are a specialized subset of Tfh cells that colocalize within B cell follicles and exhibit characteristics attributed to both Tfh cells and Treg cells, but lack expression of CD40L, IL-4, and IL-21 (74). Abrogating either follicular Treg cell development or their follicular localization was shown to enhance GC responses (7476).

Th cells were well established as a Th1/Th2 paradigm almost two decades ago. In the new millennium, IL-17–producing Th cells were identified as a subset distinct from Th1 and Th2, and the generation of these cells was shown to be mutually antagonistic with Foxp3+ Treg cells (7779). With the excitement generated by this discovery, new reports amassed rapidly of other Th subsets that selectively produce IL-22 (Th22) (80) and IL-9 (Th9) (81, 82) as well as other regulatory subsets (regulatory type 1 T cells, Th3) (28, 83, 84). During this time, Tfh cells were also reported to be a distinct lineage (8). However, the understanding of Th cell differentiation has shifted toward a view that acknowledges the flexibility of Th cell phenotypes as well as the cooperation of different T cell subsets during an immune response (Fig. 1).

One mechanism by which IL-21 drives autoimmunity is by expanding and promoting the survival of pathogenic T cell subsets in nonlymphoid tissue. Our previous work showed that autoimmune-susceptible mice produce more IL-21 compared with autoimmune-resistant strains (9, 16) and that IL-21–producing T cells increased with progression of autoimmunity (10). Furthermore, we showed that the requirement for IL-21 for islet inflammation was continuous to sustain the inflammation (25). Blockade of IL-21 led to a significant reduction in the inflammatory infiltrates into the islets, and islet graft rejection mediated by CD8 T cells was found to be IL-21–dependent (25). Similarly, Il21r−/− NOD mice fail to develop insulitis and are protected from T1D (2224). Further supporting a role for IL-21 in driving autoimmunity, diabetes could be induced by overexpression of IL-21 in the islets, even on a diabetes-resistant background (24). We recently reported that NOD mice deficient in IL-21 signaling exhibit a Treg cell/Th17 ratio skewed in favor of Treg cells (14). This observation is in line with IL-21 promoting Th17 cells while concomitantly inhibiting the induction of Treg cells (2, 4).

IL-21 can also act on parenchymal cells to promote inflammation. For example, colonic myofibroblasts and epithelial cells respond to IL-21 by secreting matrix metalloproteases as well as producing chemokines to recruit other inflammatory cells in IBD (85). In the gut mucosa, IL-21–producing Th cells are elevated in Crohn’s disease and ulcerative colitis. Although IL-21–producing Th cells coexpressing CXCR5 as well as IL-17 were identified, most were found to coproduce IFN-γ (86). IL-21+ Tfh cells in mucosal tissues, but not blood, were observed to be higher in Crohn’s disease compared with healthy controls (86). This study also showed an increase in Th17 cells in the lamina propria of IBD patients.

Excessive numbers of Tfh cells lead to autoimmunity, as evidenced in the sanroque mice carrying a mutation in the Roquin ubiquitin ligase gene (87). Roquin was identified as a negative regulator of ICOS and Tfh cells. This mutation causes an increased accumulation of Tfh cells and elevated autoantibody production that manifest as an SLE-like disease. Indeed, it has been reported that Tfh cells are required for development of Ab-mediated autoimmunity (88). BXSB mice carrying a Yaa mutation develop severe SLE; however, IL-21R–deficient BXSB-Yaa mice do not develop autoimmunity and lack characteristic features, including spontaneous GC formation, hypergammaglobulinemia, and kidney pathology (18). CCR9+ IL-21–producing Th cells are also associated with autoimmune disorders (10). This subset is enriched in blood and accessory organs of the gastrointestinal tract of mice prone to autoimmunity, namely in the pancreas, pancreatic draining lymph node, PP, and salivary gland. In patients with Sjögren’s syndrome, we reported elevated frequencies of CCR9+ Th cells in the peripheral blood (10).

The first evidence that Th17 cells, rather than Th1 cells, were the key drivers of autoimmunity in the CNS stemmed from studies using an EAE mouse model (51). Since then, Th17 cells have been found to be critically important in autoimmune disorders targeting other organs; mice with a Th17 defect owing to deficiencies in mediators that promote, or are produced by, Th17 cells were protected against many autoimmune diseases, including EAE, RA, and T1D (4, 14, 2224, 68, 69, 89, 90). Therefore, Th17-targeted therapies have been developed and under clinical trials, including anti–IL-17A mAbs for the treatment of autoimmune diseases such as psoriasis and RA (91).

The capacity for IL-21 to influence the survival and differentiation of both T cells and B cells makes it an attractive target for therapeutic intervention in a wide range of inflammatory diseases. Antagonizing IL-21 in conjunction with islet transplantation is a promising strategy to treat T1D. Blockade of IL-21 halts inflammatory destruction of insulin-producing β cells and prevents islet graft rejection; the combined treatment allowed the mice to regain endogenous β cell function (25). Antagonizing the function of IL-21 is also a promising therapy for IBD, as this has been reported to reduce disease development (21).

IL-21 is a pleiotropic cytokine produced at different stages and immunological sites of an immune response. The requirements for IL-21 production and the generation of Th cells that produce it are disease- and tissue-specific. Emerging data describing the plasticity of Th cells are helping us reconcile and explain the conclusions drawn from earlier studies. During a specific Th program, IL-21–producing T cells can express patterns of markers, cytokines, and transcription factors functionally specific for a particular response, and concomitantly express molecules that are antagonistic to other programs, conserving the ability to take cues from changing microenvironmental factors during the course of an immune response.

Abbreviations used in this article:

EAE

experimental autoimmune encephalomyelitis

eYFP

enhanced yellow fluorescent protein

GC

germinal center

IBD

inflammatory bowel disease

PD-1

programmed cell death 1

PP

Peyer’s patches

RA

rheumatoid arthritis

ROR

retinoic acid–related orphan receptor

SLE

systemic lupus erythematosus

T1D

type 1 diabetes

Tfh

T follicular helper

Treg

regulatory T.

1
Spolski
R.
,
Leonard
W. J.
.
2008
.
Interleukin-21: basic biology and implications for cancer and autoimmunity.
Annu. Rev. Immunol.
26
:
57
79
.
2
Nurieva
R.
,
Yang
X. O.
,
Martinez
G.
,
Zhang
Y.
,
Panopoulos
A. D.
,
Ma
L.
,
Schluns
K.
,
Tian
Q.
,
Watowich
S. S.
,
Jetten
A. M.
,
Dong
C.
.
2007
.
Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.
Nature
448
:
480
483
.
3
Sutton
C. E.
,
Lalor
S. J.
,
Sweeney
C. M.
,
Brereton
C. F.
,
Lavelle
E. C.
,
Mills
K. H.
.
2009
.
Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity.
Immunity
31
:
331
341
.
4
Korn
T.
,
Bettelli
E.
,
Gao
W.
,
Awasthi
A.
,
Jäger
A.
,
Strom
T. B.
,
Oukka
M.
,
Kuchroo
V. K.
.
2007
.
IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells.
Nature
448
:
484
487
.
5
Zhou
L.
,
Ivanov
I. I.
,
Spolski
R.
,
Min
R.
,
Shenderov
K.
,
Egawa
T.
,
Levy
D. E.
,
Leonard
W. J.
,
Littman
D. R.
.
2007
.
IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
Nat. Immunol.
8
:
967
974
.
6
Vogelzang
A.
,
McGuire
H. M.
,
Yu
D.
,
Sprent
J.
,
Mackay
C. R.
,
King
C.
.
2008
.
A fundamental role for interleukin-21 in the generation of T follicular helper cells.
Immunity
29
:
127
137
.
7
Fröhlich
A.
,
Marsland
B. J.
,
Sonderegger
I.
,
Kurrer
M.
,
Hodge
M. R.
,
Harris
N. L.
,
Kopf
M.
.
2007
.
IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo.
Blood
109
:
2023
2031
.
8
Nurieva
R. I.
,
Chung
Y.
,
Hwang
D.
,
Yang
X. O.
,
Kang
H. S.
,
Ma
L.
,
Wang
Y. H.
,
Watowich
S. S.
,
Jetten
A. M.
,
Tian
Q.
,
Dong
C.
.
2008
.
Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages.
Immunity
29
:
138
149
.
9
King
C.
,
Ilic
A.
,
Koelsch
K.
,
Sarvetnick
N.
.
2004
.
Homeostatic expansion of T cells during immune insufficiency generates autoimmunity.
Cell
117
:
265
277
.
10
McGuire
H. M.
,
Vogelzang
A.
,
Ma
C. S.
,
Hughes
W. E.
,
Silveira
P. A.
,
Tangye
S. G.
,
Christ
D.
,
Fulcher
D.
,
Falcone
M.
,
King
C.
.
2011
.
A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity.
Immunity
34
:
602
615
.
11
Allard
E. L.
,
Hardy
M. P.
,
Leignadier
J.
,
Marquis
M.
,
Rooney
J.
,
Lehoux
D.
,
Labrecque
N.
.
2007
.
Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation.
Eur. J. Immunol.
37
:
3069
3077
.
12
Sutherland
A. P.
,
Joller
N.
,
Michaud
M.
,
Liu
S. M.
,
Kuchroo
V. K.
,
Grusby
M. J.
.
2013
.
IL-21 promotes CD8+ CTL activity via the transcription factor T-bet.
J. Immunol.
190
:
3977
3984
.
13
Parrish-Novak
J.
,
Dillon
S. R.
,
Nelson
A.
,
Hammond
A.
,
Sprecher
C.
,
Gross
J. A.
,
Johnston
J.
,
Madden
K.
,
Xu
W.
,
West
J.
, et al
.
2000
.
Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.
Nature
408
:
57
63
.
14
Liu
S. M.
,
Lee
D. H.
,
Sullivan
J. M.
,
Chung
D.
,
Jäger
A.
,
Shum
B. O.
,
Sarvetnick
N. E.
,
Anderson
A. C.
,
Kuchroo
V. K.
.
2011
.
Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice.
J. Clin. Invest.
121
:
4303
4310
.
15
Leonard
W. J.
,
Spolski
R.
.
2005
.
Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation.
Nat. Rev. Immunol.
5
:
688
698
.
16
McGuire
H. M.
,
Vogelzang
A.
,
Hill
N.
,
Flodström-Tullberg
M.
,
Sprent
J.
,
King
C.
.
2009
.
Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus.
Proc. Natl. Acad. Sci. USA
106
:
19438
19443
.
17
Ozaki
K.
,
Spolski
R.
,
Ettinger
R.
,
Kim
H. P.
,
Wang
G.
,
Qi
C. F.
,
Hwu
P.
,
Shaffer
D. J.
,
Akilesh
S.
,
Roopenian
D. C.
, et al
.
2004
.
Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6.
J. Immunol.
173
:
5361
5371
.
18
Bubier
J. A.
,
Sproule
T. J.
,
Foreman
O.
,
Spolski
R.
,
Shaffer
D. J.
,
Morse
H. C.
 III
,
Leonard
W. J.
,
Roopenian
D. C.
.
2009
.
A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice.
Proc. Natl. Acad. Sci. USA
106
:
1518
1523
.
19
Monteleone
G.
,
Monteleone
I.
,
Fina
D.
,
Vavassori
P.
,
Del Vecchio Blanco
G.
,
Caruso
R.
,
Tersigni
R.
,
Alessandroni
L.
,
Biancone
L.
,
Naccari
G. C.
, et al
.
2005
.
Interleukin-21 enhances T-helper cell type I signaling and interferon-γ production in Crohn’s disease.
Gastroenterology
128
:
687
694
.
20
Fina
D.
,
Sarra
M.
,
Fantini
M. C.
,
Rizzo
A.
,
Caruso
R.
,
Caprioli
F.
,
Stolfi
C.
,
Cardolini
I.
,
Dottori
M.
,
Boirivant
M.
, et al
.
2008
.
Regulation of gut inflammation and Th17 cell response by interleukin-21.
Gastroenterology
134
:
1038
1048
.
21
De Nitto
D.
,
Sarra
M.
,
Pallone
F.
,
Monteleone
G.
.
2010
.
Interleukin-21 triggers effector cell responses in the gut.
World J. Gastroenterol.
16
:
3638
3641
.
22
Spolski
R.
,
Kashyap
M.
,
Robinson
C.
,
Yu
Z.
,
Leonard
W. J.
.
2008
.
IL-21 signaling is critical for the development of type I diabetes in the NOD mouse.
Proc. Natl. Acad. Sci. USA
105
:
14028
14033
.
23
Datta
S.
,
Sarvetnick
N. E.
.
2008
.
IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms.
PLoS ONE
3
:
e3118
.
24
Sutherland
A. P.
,
Van Belle
T.
,
Wurster
A. L.
,
Suto
A.
,
Michaud
M.
,
Zhang
D.
,
Grusby
M. J.
,
von Herrath
M.
.
2009
.
IL-21 is required for the development of type 1 diabetes in NOD mice.
Diabetes
58
:
1114
1155
.
25
McGuire
H. M.
,
Walters
S.
,
Vogelzang
A.
,
Lee
C. M.
,
Webster
K. E.
,
Sprent
J.
,
Christ
D.
,
Grey
S.
,
King
C.
.
2011
.
Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models.
Diabetes
60
:
867
875
.
26
Herber
D.
,
Brown
T. P.
,
Liang
S.
,
Young
D. A.
,
Collins
M.
,
Dunussi-Joannopoulos
K.
.
2007
.
IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression.
J. Immunol.
178
:
3822
3830
.
27
Young
D. A.
,
Hegen
M.
,
Ma
H. L.
,
Whitters
M. J.
,
Albert
L. M.
,
Lowe
L.
,
Senices
M.
,
Wu
P. W.
,
Sibley
B.
,
Leathurby
Y.
, et al
.
2007
.
Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis.
Arthritis Rheum.
56
:
1152
1163
.
28
Spolski
R.
,
Kim
H. P.
,
Zhu
W.
,
Levy
D. E.
,
Leonard
W. J.
.
2009
.
IL-21 mediates suppressive effects via its induction of IL-10.
J. Immunol.
182
:
2859
2867
.
29
Pot
C.
,
Jin
H.
,
Awasthi
A.
,
Liu
S. M.
,
Lai
C. Y.
,
Madan
R.
,
Sharpe
A. H.
,
Karp
C. L.
,
Miaw
S. C.
,
Ho
I. C.
,
Kuchroo
V. K.
.
2009
.
Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells.
J. Immunol.
183
:
797
801
.
30
Lüthje
K.
,
Kallies
A.
,
Shimohakamada
Y.
,
Belz
G. T.
,
Light
A.
,
Tarlinton
D. M.
,
Nutt
S. L.
.
2012
.
The development and fate of follicular helper T cells defined by an IL-21 reporter mouse.
Nat. Immunol.
13
:
491
498
.
31
King
C.
2009
.
New insights into the differentiation and function of T follicular helper cells.
Nat. Rev. Immunol.
9
:
757
766
.
32
Gunn
M. D.
,
Ngo
V. N.
,
Ansel
K. M.
,
Ekland
E. H.
,
Cyster
J. G.
,
Williams
L. T.
.
1998
.
A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1.
Nature
391
:
799
803
.
33
Cyster
J. G.
,
Ansel
K. M.
,
Reif
K.
,
Ekland
E. H.
,
Hyman
P. L.
,
Tang
H. L.
,
Luther
S. A.
,
Ngo
V. N.
.
2000
.
Follicular stromal cells and lymphocyte homing to follicles.
Immunol. Rev.
176
:
181
193
.
34
Fazilleau
N.
,
McHeyzer-Williams
L. J.
,
Rosen
H.
,
McHeyzer-Williams
M. G.
.
2009
.
The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding.
Nat. Immunol.
10
:
375
384
.
35
Deenick
E. K.
,
Chan
A.
,
Ma
C. S.
,
Gatto
D.
,
Schwartzberg
P. L.
,
Brink
R.
,
Tangye
S. G.
.
2010
.
Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling.
Immunity
33
:
241
253
.
36
Kerfoot
S. M.
,
Yaari
G.
,
Patel
J. R.
,
Johnson
K. L.
,
Gonzalez
D. G.
,
Kleinstein
S. H.
,
Haberman
A. M.
.
2011
.
Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone.
Immunity
34
:
947
960
.
37
Chtanova
T.
,
Tangye
S. G.
,
Newton
R.
,
Frank
N.
,
Hodge
M. R.
,
Rolph
M. S.
,
Mackay
C. R.
.
2004
.
T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells.
J. Immunol.
173
:
68
78
.
38
Ozaki
K.
,
Spolski
R.
,
Feng
C. G.
,
Qi
C. F.
,
Cheng
J.
,
Sher
A.
,
Morse
H. C.
 III
,
Liu
C.
,
Schwartzberg
P. L.
,
Leonard
W. J.
.
2002
.
A critical role for IL-21 in regulating immunoglobulin production.
Science
298
:
1630
1634
.
39
Eto
D.
,
Lao
C.
,
DiToro
D.
,
Barnett
B.
,
Escobar
T. C.
,
Kageyama
R.
,
Yusuf
I.
,
Crotty
S.
.
2011
.
IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.
PLoS ONE
6
:
e17739
.
40
Karnowski
A.
,
Chevrier
S.
,
Belz
G. T.
,
Mount
A.
,
Emslie
D.
,
D’Costa
K.
,
Tarlinton
D. M.
,
Kallies
A.
,
Corcoran
L. M.
.
2012
.
B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1.
J. Exp. Med.
209
:
2049
2064
.
41
Rasheed
M. A.
,
Latner
D. R.
,
Aubert
R. D.
,
Gourley
T.
,
Spolski
R.
,
Davis
C. W.
,
Langley
W. A.
,
Ha
S. J.
,
Ye
L.
,
Sarkar
S.
, et al
.
2013
.
Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells.
J. Virol.
87
:
7737
7746
.
42
Linterman
M. A.
,
Liston
A.
,
Vinuesa
C. G.
.
2012
.
T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells.
Immunol. Rev.
247
:
143
159
.
43
Kwon
H.
,
Thierry-Mieg
D.
,
Thierry-Mieg
J.
,
Kim
H. P.
,
Oh
J.
,
Tunyaplin
C.
,
Carotta
S.
,
Donovan
C. E.
,
Goldman
M. L.
,
Tailor
P.
, et al
.
2009
.
Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors.
Immunity
31
:
941
952
.
44
Bauquet
A. T.
,
Jin
H.
,
Paterson
A. M.
,
Mitsdoerffer
M.
,
Ho
I. C.
,
Sharpe
A. H.
,
Kuchroo
V. K.
.
2009
.
The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells.
Nat. Immunol.
10
:
167
175
.
45
Ma
C. S.
,
Avery
D. T.
,
Chan
A.
,
Batten
M.
,
Bustamante
J.
,
Boisson-Dupuis
S.
,
Arkwright
P. D.
,
Kreins
A. Y.
,
Averbuch
D.
,
Engelhard
D.
, et al
.
2012
.
Functional STAT3 deficiency compromises the generation of human T follicular helper cells.
Blood
119
:
3997
4008
.
46
Batten
M.
,
Ramamoorthi
N.
,
Kljavin
N. M.
,
Ma
C. S.
,
Cox
J. H.
,
Dengler
H. S.
,
Danilenko
D. M.
,
Caplazi
P.
,
Wong
M.
,
Fulcher
D. A.
, et al
.
2010
.
IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells.
J. Exp. Med.
207
:
2895
2906
.
47
Suto
A.
,
Kashiwakuma
D.
,
Kagami
S.
,
Hirose
K.
,
Watanabe
N.
,
Yokote
K.
,
Saito
Y.
,
Nakayama
T.
,
Grusby
M. J.
,
Iwamoto
I.
,
Nakajima
H.
.
2008
.
Development and characterization of IL-21-producing CD4+ T cells.
J. Exp. Med.
205
:
1369
1379
.
48
Reinhardt
R. L.
,
Liang
H. E.
,
Locksley
R. M.
.
2009
.
Cytokine-secreting follicular T cells shape the antibody repertoire.
Nat. Immunol.
10
:
385
393
.
49
Hsu
H. C.
,
Yang
P.
,
Wang
J.
,
Wu
Q.
,
Myers
R.
,
Chen
J.
,
Yi
J.
,
Guentert
T.
,
Tousson
A.
,
Stanus
A. L.
, et al
.
2008
.
Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice.
Nat. Immunol.
9
:
166
175
.
50
Korn
T.
,
Bettelli
E.
,
Oukka
M.
,
Kuchroo
V. K.
.
2009
.
IL-17 and Th17 cells.
Annu. Rev. Immunol.
27
:
485
517
.
51
Cua
D. J.
,
Sherlock
J.
,
Chen
Y.
,
Murphy
C. A.
,
Joyce
B.
,
Seymour
B.
,
Lucian
L.
,
To
W.
,
Kwan
S.
,
Churakova
T.
, et al
.
2003
.
Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
Nature
421
:
744
748
.
52
Bettelli
E.
,
Korn
T.
,
Oukka
M.
,
Kuchroo
V. K.
.
2008
.
Induction and effector functions of TH17 cells.
Nature
453
:
1051
1057
.
53
McGeachy
M. J.
,
Bak-Jensen
K. S.
,
Chen
Y.
,
Tato
C. M.
,
Blumenschein
W.
,
McClanahan
T.
,
Cua
D. J.
.
2007
.
TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology.
Nat. Immunol.
8
:
1390
1397
.
54
Lee
Y.
,
Awasthi
A.
,
Yosef
N.
,
Quintana
F. J.
,
Xiao
S.
,
Peters
A.
,
Wu
C.
,
Kleinewietfeld
M.
,
Kunder
S.
,
Hafler
D. A.
, et al
.
2012
.
Induction and molecular signature of pathogenic TH17 cells.
Nat. Immunol.
13
:
991
999
.
55
Coquet
J. M.
,
Chakravarti
S.
,
Smyth
M. J.
,
Godfrey
D. I.
.
2008
.
Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis.
J. Immunol.
180
:
7097
7101
.
56
Sonderegger
I.
,
Kisielow
J.
,
Meier
R.
,
King
C.
,
Kopf
M.
.
2008
.
IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo.
Eur. J. Immunol.
38
:
1833
1838
.
57
Ivanov
I. I.
,
McKenzie
B. S.
,
Zhou
L.
,
Tadokoro
C. E.
,
Lepelley
A.
,
Lafaille
J. J.
,
Cua
D. J.
,
Littman
D. R.
.
2006
.
The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells.
Cell
126
:
1121
1133
.
58
Huber
M.
,
Brüstle
A.
,
Reinhard
K.
,
Guralnik
A.
,
Walter
G.
,
Mahiny
A.
,
von Löw
E.
,
Lohoff
M.
.
2008
.
IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype.
Proc. Natl. Acad. Sci. USA
105
:
20846
20851
.
59
Brüstle
A.
,
Heink
S.
,
Huber
M.
,
Rosenplänter
C.
,
Stadelmann
C.
,
Yu
P.
,
Arpaia
E.
,
Mak
T. W.
,
Kamradt
T.
,
Lohoff
M.
.
2007
.
The development of inflammatory TH-17 cells requires interferon-regulatory factor 4.
Nat. Immunol.
8
:
958
966
.
60
Zheng
Y.
,
Danilenko
D. M.
,
Valdez
P.
,
Kasman
I.
,
Eastham-Anderson
J.
,
Wu
J.
,
Ouyang
W.
.
2007
.
Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
Nature
445
:
648
651
.
61
Ma
C. S.
,
Chew
G. Y.
,
Simpson
N.
,
Priyadarshi
A.
,
Wong
M.
,
Grimbacher
B.
,
Fulcher
D. A.
,
Tangye
S. G.
,
Cook
M. C.
.
2008
.
Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.
J. Exp. Med.
205
:
1551
1557
.
62
de Beaucoudrey
L.
,
Puel
A.
,
Filipe-Santos
O.
,
Cobat
A.
,
Ghandil
P.
,
Chrabieh
M.
,
Feinberg
J.
,
von Bernuth
H.
,
Samarina
A.
,
Jannière
L.
, et al
.
2008
.
Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.
J. Exp. Med.
205
:
1543
1550
.
63
Milner
J. D.
,
Brenchley
J. M.
,
Laurence
A.
,
Freeman
A. F.
,
Hill
B. J.
,
Elias
K. M.
,
Kanno
Y.
,
Spalding
C.
,
Elloumi
H. Z.
,
Paulson
M. L.
, et al
.
2008
.
Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.
Nature
452
:
773
776
.
64
Hirota
K.
,
Turner
J. E.
,
Villa
M.
,
Duarte
J. H.
,
Demengeot
J.
,
Steinmetz
O. M.
,
Stockinger
B.
.
2013
.
Plasticity of Th17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses.
Nat. Immunol.
14
:
372
379
.
65
Mitsdoerffer
M.
,
Lee
Y.
,
Jäger
A.
,
Kim
H. J.
,
Korn
T.
,
Kolls
J. K.
,
Cantor
H.
,
Bettelli
E.
,
Kuchroo
V. K.
.
2010
.
Proinflammatory T helper type 17 cells are effective B-cell helpers.
Proc. Natl. Acad. Sci. USA
107
:
14292
14297
.
66
Vinuesa
C. G.
,
Cyster
J. G.
.
2011
.
How T cells earn the follicular rite of passage.
Immunity
35
:
671
680
.
67
Paulos
C. M.
,
Carpenito
C.
,
Plesa
G.
,
Suhoski
M. M.
,
Varela-Rohena
A.
,
Golovina
T. N.
,
Carroll
R. G.
,
Riley
J. L.
,
June
C. H.
.
2010
.
The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells.
Sci. Transl. Med.
2
:
55ra78
.
68
Bending
D.
,
De la Peña
H.
,
Veldhoen
M.
,
Phillips
J. M.
,
Uyttenhove
C.
,
Stockinger
B.
,
Cooke
A.
.
2009
.
Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice.
J. Clin. Invest.
119
:
565
572
.
69
Martin-Orozco
N.
,
Chung
Y.
,
Chang
S. H.
,
Wang
Y. H.
,
Dong
C.
.
2009
.
Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells.
Eur. J. Immunol.
39
:
216
224
.
70
Esplugues
E.
,
Huber
S.
,
Gagliani
N.
,
Hauser
A. E.
,
Town
T.
,
Wan
Y. Y.
,
O’Connor
W.
 Jr.
,
Rongvaux
A.
,
Van Rooijen
N.
,
Haberman
A. M.
, et al
.
2011
.
Control of TH17 cells occurs in the small intestine.
Nature
475
:
514
518
.
71
Hirota
K.
,
Duarte
J. H.
,
Veldhoen
M.
,
Hornsby
E.
,
Li
Y.
,
Cua
D. J.
,
Ahlfors
H.
,
Wilhelm
C.
,
Tolaini
M.
,
Menzel
U.
, et al
.
2011
.
Fate mapping of IL-17-producing T cells in inflammatory responses.
Nat. Immunol.
12
:
255
263
.
72
Crotty
S.
2011
.
Follicular helper CD4 T cells (TFH).
Annu. Rev. Immunol.
29
:
621
663
.
73
Tsuji
M.
,
Komatsu
N.
,
Kawamoto
S.
,
Suzuki
K.
,
Kanagawa
O.
,
Honjo
T.
,
Hori
S.
,
Fagarasan
S.
.
2009
.
Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches.
Science
323
:
1488
1492
.
74
Linterman
M. A.
,
Pierson
W.
,
Lee
S. K.
,
Kallies
A.
,
Kawamoto
S.
,
Rayner
T. F.
,
Srivastava
M.
,
Divekar
D. P.
,
Beaton
L.
,
Hogan
J. J.
, et al
.
2011
.
Foxp3+ follicular regulatory T cells control the germinal center response.
Nat. Med.
17
:
975
982
.
75
Chung
Y.
,
Tanaka
S.
,
Chu
F.
,
Nurieva
R. I.
,
Martinez
G. J.
,
Rawal
S.
,
Wang
Y. H.
,
Lim
H.
,
Reynolds
J. M.
,
Zhou
X. H.
, et al
.
2011
.
Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions.
Nat. Med.
17
:
983
988
.
76
Wollenberg
I.
,
Agua-Doce
A.
,
Hernández
A.
,
Almeida
C.
,
Oliveira
V. G.
,
Faro
J.
,
Graca
L.
.
2011
.
Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells.
J. Immunol.
187
:
4553
4560
.
77
Harrington
L. E.
,
Hatton
R. D.
,
Mangan
P. R.
,
Turner
H.
,
Murphy
T. L.
,
Murphy
K. M.
,
Weaver
C. T.
.
2005
.
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
Nat. Immunol.
6
:
1123
1132
.
78
Park
H.
,
Li
Z.
,
Yang
X. O.
,
Chang
S. H.
,
Nurieva
R.
,
Wang
Y. H.
,
Wang
Y.
,
Hood
L.
,
Zhu
Z.
,
Tian
Q.
,
Dong
C.
.
2005
.
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
Nat. Immunol.
6
:
1133
1141
.
79
Bettelli
E.
,
Carrier
Y.
,
Gao
W.
,
Korn
T.
,
Strom
T. B.
,
Oukka
M.
,
Weiner
H. L.
,
Kuchroo
V. K.
.
2006
.
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
Nature
441
:
235
238
.
80
Eyerich
S.
,
Eyerich
K.
,
Pennino
D.
,
Carbone
T.
,
Nasorri
F.
,
Pallotta
S.
,
Cianfarani
F.
,
Odorisio
T.
,
Traidl-Hoffmann
C.
,
Behrendt
H.
, et al
.
2009
.
Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.
J. Clin. Invest.
119
:
3573
3585
.
81
Dardalhon
V.
,
Awasthi
A.
,
Kwon
H.
,
Galileos
G.
,
Gao
W.
,
Sobel
R. A.
,
Mitsdoerffer
M.
,
Strom
T. B.
,
Elyaman
W.
,
Ho
I. C.
, et al
.
2008
.
IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3 effector T cells.
Nat. Immunol.
9
:
1347
1355
.
82
Veldhoen
M.
,
Uyttenhove
C.
,
van Snick
J.
,
Helmby
H.
,
Westendorf
A.
,
Buer
J.
,
Martin
B.
,
Wilhelm
C.
,
Stockinger
B.
.
2008
.
Transforming growth factor-β “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset.
Nat. Immunol.
9
:
1341
1346
.
83
Awasthi
A.
,
Carrier
Y.
,
Peron
J. P.
,
Bettelli
E.
,
Kamanaka
M.
,
Flavell
R. A.
,
Kuchroo
V. K.
,
Oukka
M.
,
Weiner
H. L.
.
2007
.
A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells.
Nat. Immunol.
8
:
1380
1389
.
84
Carrier
Y.
,
Yuan
J.
,
Kuchroo
V. K.
,
Weiner
H. L.
.
2007
.
Th3 cells in peripheral tolerance. II. TGF-β-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity.
J. Immunol.
178
:
172
178
.
85
Monteleone
G.
,
Caruso
R.
,
Fina
D.
,
Peluso
I.
,
Gioia
V.
,
Stolfi
C.
,
Fantini
M. C.
,
Caprioli
F.
,
Tersigni
R.
,
Alessandroni
L.
, et al
.
2006
.
Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21.
Gut
55
:
1774
1780
.
86
Sarra
M.
,
Monteleone
I.
,
Stolfi
C.
,
Fantini
M. C.
,
Sileri
P.
,
Sica
G.
,
Tersigni
R.
,
Macdonald
T. T.
,
Pallone
F.
,
Monteleone
G.
.
2010
.
Interferon-γ-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases.
Inflamm. Bowel Dis.
16
:
1332
1339
.
87
Vinuesa
C. G.
,
Cook
M. C.
,
Angelucci
C.
,
Athanasopoulos
V.
,
Rui
L.
,
Hill
K. M.
,
Yu
D.
,
Domaschenz
H.
,
Whittle
B.
,
Lambe
T.
, et al
.
2005
.
A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity.
Nature
435
:
452
458
.
88
Linterman
M. A.
,
Rigby
R. J.
,
Wong
R. K.
,
Yu
D.
,
Brink
R.
,
Cannons
J. L.
,
Schwartzberg
P. L.
,
Cook
M. C.
,
Walters
G. D.
,
Vinuesa
C. G.
.
2009
.
Follicular helper T cells are required for systemic autoimmunity.
J. Exp. Med.
206
:
561
576
.
89
Murphy
C. A.
,
Langrish
C. L.
,
Chen
Y.
,
Blumenschein
W.
,
McClanahan
T.
,
Kastelein
R. A.
,
Sedgwick
J. D.
,
Cua
D. J.
.
2003
.
Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
J. Exp. Med.
198
:
1951
1957
.
90
Emamaullee
J. A.
,
Davis
J.
,
Merani
S.
,
Toso
C.
,
Elliott
J. F.
,
Thiesen
A.
,
Shapiro
A. M.
.
2009
.
Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.
Diabetes
58
:
1302
1311
.
91
Reichert
J. M.
2013
.
Which are the antibodies to watch in 2013?
MAbs
5
:
1
4
.

The authors have no financial conflicts of interest.