Download Recent advances in IL

International Immunology, Vol. 23, No. 3, pp. 159–163
doi:10.1093/intimm/dxr001
ª The Japanese Society for Immunology. 2011. All rights reserved.
For permissions, please e-mail: [email protected]
Recent advances in IL-22 biology
Lauren A. Zenewicz1 and Richard A. Flavell1,2
1
Department of Immunobiology and 2Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street,
TAC S-569, New Haven,
CT 06520, USA
Received 12 November 2010, accepted 5 January 2011
Abstract
Several cell types, in particular epithelial cells, express the receptor for the cytokine IL-22 and upon its
recognition produce molecules that are active both locally and systemically. Many different types of
lymphocyte secrete IL-22. Th17 cells produce IL-22 although the optimal conditions for secretion of
IL-17 or IL-22 by Th17 cells differ, as do the transcription factors involved. Aryl hydrocarbon receptor
is required for IL-22 production by Th17, Th22 and gd T cells. Th22 cells produce IL-22 in response to
IL-6 and tumor necrosis factor a (TNF-a), particularly in the skin, whereas gd T cells produce IL-22 in
response to IL-23, particularly in the lung. NK cells produce IL-22 in response to IL-12 and IL-18 or
IL-23. Retinoic acid-related orphan receptorgt-positive innate lymphoid cells, including lymphoid
tissue inducer (LTi) and LTi-like cells express IL-22 with IL-23 again enhancing expression. IL-22 is
known to be expressed in many chronic inflammatory conditions, including psoriasis and rheumatoid
arthritis, and its up-regulation often correlates with disease activity. IL-22 is known to be protective in
the gastrointestinal tract in inflammatory bowel disease but may mediate either harmful or helpful
inflammatory responses in different models of intestinal infection. Finally, IL-22 may also play an
important role in tissue repair.
Introduction
IL-22 is a cytokine that is important for the modulation of
tissue responses during inflammation. Through activation of
Stat3-signaling cascades, the cytokine induces proliferative
and anti-apoptotic pathways, as well as anti-microbial molecules, that help prevent tissue damage and aid in its repair.
IL-22 is expressed by both the adaptive arm of the immune
system, such as CD4 T-cell subsets, as well as by innate lymphocytes, including NK cells and LTi-like cells. IL-22 plays an
important role in inflammation, including chronic inflammatory
diseases and infectious diseases. This review focuses on new
findings on the cell subsets that express IL-22 and its functional
role during inflammation.
effects due to systemic induction (i.e. SAA in sera). IL-22 also
induces proliferative and anti-apoptotic pathways in responsive cells allowing for tissue preservation (8).
The expression of IL-22 in cells of the immune system
IL-22 is expressed by many different types of lymphocytes,
including both those of the innate and adaptive immune system. This includes CD4 T cells, most notably Th17 cells, and
cd T cells, NK cells, LTi cells and LTi-like cells. Regulation of
IL-22 expression by these different subsets has some common qualities, such as similar activation receptors and transcription factors, but there are also unique mechanisms.
Cells that respond to IL-22
IL-22 is recognized by a heterodimeric receptor consisting of
IL-22R and IL-10Rb (1, 2); the expression of IL-22R is mainly
confined to epithelial cells, thus providing signaling specificity
to tissues (3). The best characterized IL-22-target cells include
keratinocytes, hepatocytes and colonic epithelial cells. Binding
of the cytokine to this receptor leads to activation of Stat3 signaling cascades, as well as Akt and mitogen-activated protein
kinase pathways (4). This in turn results in induction of various
tissue-specific genes, including serum amyloid A (SAA), antimicrobial proteins (b-defensin, Reg3c, lipocalin-2), and mucins
(1, 3, 5–7). These molecules have localized effects in the tissues (i.e. anti-microbials) but also have more generalized
Th17 cells
IL-22 was originally thought to be a Th1-associated cytokine but
with the discovery of Th17 cells has since been found to be
most highly expressed by this particular subset (9). IL-22 expression differs from that of IL-17A and other Th17-associated
cytokines. The ideal in vitro culture conditions for generating
IL-17A-expressing cells, mainly the presence of transforming
growth factor-b (TGF-b) and IL-6, does not lead to optimal IL22 expression; this is because TGF-b is inhibitory to IL-22 expression (10–12). IL-17A production was just revealed to be
able to occur independently of TGF-b signaling by differentiating naive T cells in the presence of IL-6, IL-23 and IL-1b and
REVIEW
Correspondence to: R. A. Flavell, E-mail: [email protected]
160 Advances in IL-22 biology
this cytokine milieu also leads to IL-22 expression (11). Furthermore, in vivo IL-22 expression during infections is dependent
on IL-23, but IL-17A expression is less so (13, 14).
IL-17A is highly dependent on the nuclear hormone receptor
transcription factors retinoic acid-related orphan receptor ct
(RORct) and RORa for its expression; IL-22 is less so (15, 16).
In contrast, IL-22 expression requires the ligand-dependent
transcription factor aryl hydrocarbon receptor (AHR) (16).
Ligands include environmental toxins, such as halogenated
aromatic hydrocarbons, and endogenous natural ligands, such
as the breakdown products of aromatic amino acids (16, 17).
Addition of these AHR ligands during in vitro culture or in vivo
during an immune response augments IL-22 expression.
Furthermore, Notch signaling induces production of endogenous AHR ligands, leading to greater IL-22 expression (18).
Th22 cells
In humans, a subset of CD4 T cells that specifically expresses
IL-22 and is mainly found in tissues has been identified.
Termed ‘Th22’ cells, these cells express the chemokine receptor CCR6, and the skin-homing receptors CCR4 and CCR10,
allowing for localization to the skin (19, 20). They do not express IFN-c or IL-17A, or the Th1- and Th17-associated transcription factors T-bet or RORct, respectively (19). Like that
described for murine Th17 cells, AHR is an important transcription factor for the expression of IL-22, but not IL-17A (20).
Inflammatory cytokines, namely IL-6 and tumor necrosis
factor a (TNF-a), promote priming of Th22 cells and addition
of active vitamin D (found in the sun-exposed skin) enhances
IL-22 expression. Langerhans cells, specialized professional
antigen-presenting cells found in the epidermis, are able to
induce Th22 cells (21), as were plasmacytoid dendritic cells
(19). Th22 T-cell clones appear to be quite stable; if cultured
in Th1-, Th2-, Th17- or Treg-polarizing conditions, the Th22
clones continue to express IL-22 and not the other cytokines
associated with these Th subsets (22). Th22 cells appear to
be important for skin homeostasis and in inflammation as the
Th22 cell population is increased in psoriasis patients (23).
gd T cells
The cd T-cell subset comprises innate T cells that have rapid
and immediate effector functions upon recognition of unknown
ligands. Unlike conventional CD4 T cells, these cells constitutively express IL-23R, and therefore immediately respond to
IL-23 stimulation to express both IL-17A and IL-22 (24). As
for Th17 and Th22 cells, AHR is an important transcription factor for the expression of IL-22, but not IL-17A (24). IL-22expressing cd T cells are particularly important in pulmonary
immune responses (25).
NK cells
NK cells are innate lymphocytes that lack somatically rearranged cell surface antigen-specific molecules and develop
independently of the transcription factor RORct. Upon activation, conventional NK cells rapidly express IFN-c, perforin
and granzymes that play an important role in the control of
viruses, intracellular bacteria and tumors. These cells can
be activated by a synergy between two cytokines, IL-12 and
IL-18, presumably secreted by macrophages activated by
antigen/innate sensor encounter. This activation by IL-12 and
IL-18 can also induce NK cells to secrete IL-22 (26, 27). Additionally, stimulation with the cytokine IL-23 leads to induction
of IL-22, but not IFN-c, in NK cells (27). These NK1.1+ IL22-expressing cells contribute to IL-22 expression during inflammatory bowel disease (IBD) (27), as well as in influenza
infection (28). Other studies have reported IL-22-secreting
NK cells termed NK22 cells (29); however, as it currently
stands, these cells are now better characterized as the LTilike IL-22-expressing cells discussed in the following section.
RORgt-positive innate lymphoid cells
LTi cells were originally discovered in the fetal tissue of mice
(30). These cells express lymphotoxin-a1b2 and other factors that are important for the stromal re-organization and
lymphocyte recruitment required for lymph node development. More recent work has shown that LTi cell development
is dependent on the transcription factor RORct and also
needed for formation of Peyer’s patches in the small intestine
(31). Although discovered in mice over 10 years ago, only
recently has a corresponding cell subset been identified in
human fetal lymph nodes and spleens (32). In discovery of
this cell subset, it was also revealed that these cells express
considerable amounts of IL-22, as well as IL-17A (32).
LTi-like cells also express IL-22 and share expression of
NK-cell and LTi markers; they express the NK-cell surface
marker NKp46 and the LTi cell transcription factor RORct
(33–35). There are strong lineage relationships between NK
cells and LTi-like cells. Both NK cells and LTi-like cells are dependent on expression of the transcription factors ID2 and
TOX for their development (36, 37). However, these cells are
dependent on different downstream transcription factors; NK
cells are dependent on E4bp4/Nfil3 (38, 39), whereas LTi-like
cells are dependent on RORct (35). Additionally, NK cells require IL-15 for their development, and IL-7 is important, but
not essential, for LTi-like cells (33, 35). An elegant new study
has performed a lineage relationship analysis of RORctexpressing innate lymphocytes (40). These cells arise from
distinct fetal liver RORct precursors and the data suggest that
LTi cells are required in the fetus for lymph node development
and after birth they undergo a programmed population
change to what has been termed LTi-like cells, to migrate to
the gastrointestinal (GI) tract to sustain intestinal homeostasis.
LTi-like cells are CD3 and express CD127, a component
of the IL-7 receptor, and IL-23R, and in mice the cells are also
CD4+. Unlike other cell subsets that only express IL-22 upon
activation, LTi-like cells express low constitutive levels of IL22 that are highly induced upon activation by IL-23 stimulation. They also express IL-17A, but not IFN-c, perforin or
granzymes (33–35, 41). In addition to being localized to the
small intestine, these cells have also been found in lymphoid
tissues such as the spleen (42).
IL-22 function
Chronic inflammatory diseases
IL-22 is highly expressed in several different chronic inflammatory conditions, including psoriasis, IBD and rheumatoid
Advances in IL-22 biology
arthritis (43–45). This up-regulation of IL-22 is a correlation
with disease; it cannot be inferred if IL-22 is a cause of the inflammation and/or a result of it. As such, small animal disease
models have been employed to help elucidate the role of IL22 in inflammation. Using either gene-deficient mice or administration of neutralizing antibodies, investigators have studied
the role of IL-22 in various inflammatory conditions. These
models have identified both inflammatory and protective roles
for IL-22.
The best studied function for IL-22 is within the skin; IL-22 is
inflammatory during skin inflammation. Transgenic mice engineered to over-express IL-22 have an aberrant skin phenotype
that resembles psoriasis (46). The IL-22 transgenic pups are
born with shiny and stiff skin and die several days post-birth.
Histological analysis of the skin reveals epidermal thickening
and that the dermal layer contains infiltrating macrophages.
Using IL-22-deficient mice, Zheng et al. showed that in the
absence of IL-22, IL-23-mediated dermal inflammation was
reduced (10). Another group has also shown that IL-22 is inflammatory in a T-cell-mediated model of psoriasis (47).
These data are consistent with in vitro studies in which
IL-22 was found to mediate keratinocyte proliferation and
epithelial hyperplasia (46, 48). Furthermore, using threedimensional epidermis culture systems, Wolk et al. showed
that IL-22 is important for epidermal remodeling (46). Thus,
though induction of proliferation, IL-22 induces keratinocyte
migration, leading to the hyperplasia of keratinocyte layers,
and results in a thickening of the epidermis.
In addition to psoriasis, an inflammatory role for IL-22 has
been found in rheumatoid arthritis (49). Using an experimental
model in which mice are immunized against collagen generating an autoimmune response in the joints, mice deficient in
IL-22 had decreased incidence of arthritis and pannus formation (49). IL-22 may promote osteoclastogenesis leading to
bone erosion in rheumatoid arthritis.
IL-22 also has a protective role in inflammation. The dual
nature of this cytokine, protective versus inflammatory, likely
depends on the inflammatory context, which includes, but is
not limited to, the duration and amount of IL-22 present,
the overall cytokine milieu and the tissues involved. IL22 has shown to be protective during hepatitis (8, 50). In
hepatocytes, IL-22 activates anti-apoptotic and pro-survival
pathways, which allows for their enhanced survival (8). IL-22expressing Th17 cells transferred to mice before induction of
hepatitis ameliorated liver injury (50). IL-22 also plays a positive role in liver regeneration and in liver lipogenesis and hepatic steatosis induced by a high-fat diet or ethanol (51–53).
IL-22 is also protective during IBD. Genome-wide linkage
analysis of IBD patients has identified mutations in the genes
encoding IL-22 and the IL-10Rb subunit of the IL-22 receptor
complex (54, 55). The IL-22 receptor complex is highly
expressed within the GI tract and in the inflamed colon, IL-22
is expressed by CD4 T cells, likely Th17 cells, and innate lymphocytes such NK cells and LTi-like cells (27). Using different
experimental models of IBD—DSS-induced colitis which is
thought to be mainly driven by innate immune response cells
and CD4+ CD45RBhigh T-cell-mediated colitis in which naive
T cells devoid of regulatory T cells are transferred into T-celldeficient mice where they proliferate unimpeded leading to
colitis—IL-22 has been shown to be protective in both cases
161
(5, 27). Furthermore, Sugimoto et al. showed that IL-22 can
be therapeutic to IBD; gene therapy transfer of the Il22 gene
into the colons of already inflamed mice resulted in amelioration of the inflammation (5).
Several molecules appear to be important for the mechanism of how IL-22 provides protection within the GI tract. IL-22
induces expression of several anti-microbial molecules in the
GI tract, including Reg3c, lipocalin-2 and b-defensins (3, 6, 7).
These proteins may be important in the control of pathogenic
micro-organisms within the gut. IL-22 also induces expression
of mucins, a large heavily glycosylated family of proteins that
forms a protective layer in the GI tract allowing for separation
of commensal and pathogenic flora from the epithelium and
hereby minimizing the immune response (5). Furthermore, IL22 has direct effects on the colonic epithelium allowing for its
proliferation and thereby contributing to its integrity.
IL-22-expressing cd T cells are important for protection from
lung fibrosis (25). Repeated antigen stimulation in the lung
leads to collagen deposition and the development of fibrosis.
In the absence of IL-22 expression, mice had significantly
more lung fibrosis than control mice, and the administration
of recombinant cytokine further reduced the production of
collagen. These data suggest that IL-22 plays a protective
role in the development of fibrosis.
Infectious diseases
IL-22 also has a function in inflammation mediated by pathogens. IL-22 can be inflammatory and mediate disease in the
GI tract. When infection by the parasite Toxoplasma gondii is
introduced via the peritoneal cavity or the bloodstream, IL-22
does not play a detectable role in its pathogenesis, including
parasite loads in the brain and liver lesions (56). In contrast,
oral inoculation of the parasite into IL-22-deficient mice results
in less disease pathology in the small intestine compared with
wild-type controls (14). Thus, IL-22 is pathogenic in the course
of T. gondii infection in the GI tract, but not other tissues.
By contributing to the maintenance of epithelial barriers,
IL-22 helps prevent dissemination of pathogenic bacteria, such
as Klebsiella pneuomniae in the lung (57), or enteropathogens, including Citrobacter rodentium and Salmonella enterica
serotype Typhimurium, in the GI tract, thereby limiting bacterial growth (6, 7). Additionally, IL-22 aids in the elimination of
pathogens by inducing different anti-microbial proteins (6, 7).
Although human data indicating a role for IL-22 in infection
are sparse, besides correlative reports showing induction of
IL-22 during diseases, there is an interesting report that suggests that IL-22 plays a role in human infection. Patients with
autoimmune polyendocrine syndrome type I have a high rate
of chronic mucocutaneous candidiasis (58). In that study
Puel et al. showed that these patients have high levels of
auto-antibodies to IL-17A and IL-22, in effect leading to cytokine neutralization and suggests that these cytokines are important for controlling yeast infections. In animal models of
candidiasis, there are conflicting reports as to the importance of IL-22 to pathogenesis (59, 60).
Tissue repair
In addition to inflammation induced by autoimmune or infectious diseases, IL-22 also plays a role in tissue repair after
162 Advances in IL-22 biology
wounding. Pickert et al. showed delayed healing of mucosal
colonic biopsies of IL-22-deficient mice compared with controls
(61). IL-22 is also important for the regeneration of liver tissue
after partial hepatectomy and repair from alcohol-induced
damage (52,53). In vitro assays have shown that IL-22 treatment of keratinocytes quickens repair after wounding (22).
Thus, IL-22 has many roles in aiding tissue repair.
Concluding remarks
Many outstanding questions regarding IL-22 and inflammation
exist. Most in vivo studies have not elucidated which IL-22expressing cell subset mediates the observed effects. For example, Th17 cells have been shown to be able to provide protection against hepatitis (50) but the study did not show if this
subset was required for protection. Other studies have distinguished between innate and adaptive immune system-derived
IL-22 by comparing models between immunocompetent mice
and mice with deficient adaptive immune responses (i.e.
Rag-deficient or scid) (6, 27). Further examination pin-pointing
the role of different IL-22-expressing subsets will allow us to
better understand this cytokine.
Second, the role of IL-22 not under inflammatory conditions, but instead during homeostasis needs to be more
closely examined. IL-22 is expressed constitutively by LTi-like
cells within the small intestine, a tissue that is under the careful immune balance between inflammation and tolerance.
Gaining a better understanding of the expression and role of
IL-22 in health and disease is important for development of
IL-22 as a potential drug target.
8
9
10
11
12
13
14
15
16
17
Funding
18
LAZ has been supported by post-doctoral fellowships from the
American Liver Foundation and the American Cancer Society.
19
Acknowledgements
RAF is an Investigator of the Howard Hughes Medical Institute.
20
References
1 Dumoutier, L., Van Roost, E., Colau, D. and Renauld, J. C. 2000.
Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocytestimulating factor. Proc. Natl Acad. Sci. USA 97:10144.
2 Xie, M. H., Aggarwal, S., Ho, W. H. et al. 2000. Interleukin (IL)-22,
a novel human cytokine that signals through the interferon
receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem.
275:31335.
3 Wolk, K., Kunz, S., Witte, E., Friedrich, M., Asadullah, K. and Sabat,
R. 2004. IL-22 increases the innate immunity of tissues. Immunity
21:241.
4 Lejeune, D., Dumoutier, L., Constantinescu, S., Kruijer, W.,
Schuringa, J. J. and Renauld, J. C. 2002. Interleukin-22 (IL-22)
activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways
in a rat hepatoma cell line. Pathways that are shared with and
distinct from IL-10. J. Biol. Chem. 277:33676.
5 Sugimoto, K., Ogawa, A., Mizoguchi, E. et al. 2008. IL-22
ameliorates intestinal inflammation in a mouse model of ulcerative
colitis. J. Clin. Invest. 118:534.
6 Zheng, Y., Valdez, P. A., Danilenko, D. M. et al. 2008. Interleukin22 mediates early host defense against attaching and effacing
bacterial pathogens. Nat. Med. 14:282.
7 Raffatellu, M., George, M. D., Akiyama, Y. et al. 2009. Lipocalin-2
resistance confers an advantage to Salmonella enterica serotype
21
22
23
24
25
26
27
Typhimurium for growth and survival in the inflamed intestine. Cell
Host Microbe. 5:476.
Radaeva, S., Sun, R., Pan, H. N., Hong, F. and Gao, B. 2004.
Interleukin 22 (IL-22) plays a protective role in T cell-mediated
murine hepatitis: IL-22 is a survival factor for hepatocytes via
STAT3 activation. Hepatology 39:1332.
Liang, S. C., Tan, X. Y., Luxenberg, D. P. et al. 2006. Interleukin
(IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med.
203:2271.
Zheng, Y., Danilenko, D. M., Valdez, P. et al. 2007. Interleukin-22,
a T(H)17 cytokine, mediates IL-23-induced dermal inflammation
and acanthosis. Nature 445:648.
Ghoreschi, K., Laurence, A., Yang, X. P. et al. 2010. Generation of
pathogenic T(H)17 cells in the absence of TGF-beta signalling.
Nature 467:967.
Volpe, E., Servant, N., Zollinger, R. et al. 2008. A critical function
for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17
responses. Nat. Immunol. 9:650.
Siegemund, S., Schutze, N., Schulz, S. et al. 2009. Differential IL23 requirement for IL-22 and IL-17A production during innate
immunity against Salmonella enterica serovar Enteritidis. Int.
Immunol. 21:555.
Munoz, M., Heimesaat, M. M., Danker, K. et al. 2009. Interleukin
(IL)-23 mediates Toxoplasma gondii-induced immunopathology in
the gut via matrixmetalloproteinase-2 and IL-22 but independent
of IL-17. J. Exp. Med. 206:3047.
Yang, X. O., Pappu, B. P., Nurieva, R. et al. 2008. T helper 17
lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28:29.
Veldhoen, M., Hirota, K., Westendorf, A. M. et al. 2008. The aryl
hydrocarbon receptor links TH17-cell-mediated autoimmunity to
environmental toxins. Nature 453:106.
Veldhoen, M., Hirota, K., Christensen, J., O’Garra, A. and
Stockinger, B. 2009. Natural agonists for aryl hydrocarbon
receptor in culture medium are essential for optimal differentiation
of Th17 T cells. J. Exp. Med. 206:43.
Alam, M. S., Maekawa, Y., Kitamura, A. et al. 2010. Notch
signaling drives IL-22 secretion in CD4+ T cells by stimulating the
aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 107:5943.
Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. and
Sallusto, F. 2009. Production of interleukin 22 but not interleukin
17 by a subset of human skin-homing memory T cells. Nat.
Immunol. 10:857.
Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. and Spits, H.
2009. Identification of a human helper T cell population that has
abundant production of interleukin 22 and is distinct from T(H)-17,
T(H)1 and T(H)2 cells. Nat. Immunol. 10:864.
Fujita, H., Nograles, K. E., Kikuchi, T., Gonzalez, J., Carucci, J. A.
and Krueger, J. G. 2009. Human Langerhans cells induce distinct
IL-22-producing CD4+ T cells lacking IL-17 production. Proc. Natl.
Acad. Sci. USA 106:21795.
Eyerich, S., Eyerich, K., Pennino, D. et al. 2009. Th22 cells
represent a distinct human T cell subset involved in epidermal
immunity and remodeling. J. Clin. Invest. 119:3573.
Kagami, S., Rizzo, H. L., Lee, J. J., Koguchi, Y. and Blauvelt, A.
2010. Circulating Th17, Th22, and Th1 cells are increased in
psoriasis. J. Invest. Dermatol 130:1373.
Martin, B., Hirota, K., Cua, D. J., Stockinger, B. and Veldhoen, M.
2009. Interleukin-17-producing gammadelta T cells selectively
expand in response to pathogen products and environmental
signals. Immunity 31:321.
Simonian, P. L., Wehrmann, F., Roark, C. L., Born, W. K., O’Brien,
R. L. and Fontenot, A. P. 2010. gammadelta T cells protect against
lung fibrosis via IL-22. J. Exp. Med. 207:2239.
Wolk, K., Kunz, S., Asadullah, K. and Sabat, R. 2002. Cutting
edge: immune cells as sources and targets of the IL-10 family
members? J. Immunol. 168:5397.
Zenewicz, L. A., Yancopoulos, G. D., Valenzuela, D. M., Murphy,
A. J., Stevens, S. and Flavell, R. A. 2008. Innate and adaptive
interleukin-22 protects mice from inflammatory bowel disease.
Immunity 29:947.
Advances in IL-22 biology
28 Guo, H. and Topham, D. J. 2010. Interleukin-22 (IL-22) production
by pulmonary Natural Killer cells and the potential role of IL-22
during primary influenza virus infection. J. Virol. 84:7750.
29 Cella, M., Fuchs, A., Vermi, W. et al. 2009. A human natural killer
cell subset provides an innate source of IL-22 for mucosal
immunity. Nature 457:722.
30 Mebius, R. E., Rennert, P. and Weissman, I. L. 1997. Developing
lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells.
Immunity 7:493.
31 Eberl, G., Marmon, S., Sunshine, M. J., Rennert, P. D., Choi, Y. and
Littman, D. R. 2004. An essential function for the nuclear receptor
RORgamma(t) in the generation of fetal lymphoid tissue inducer
cells. Nat. Immunol. 5:64.
32 Cupedo, T., Crellin, N. K., Papazian, N. et al. 2009. Human fetal
lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol.
10:66.
33 Satoh-Takayama, N., Vosshenrich, C. A., Lesjean-Pottier, S. et al.
2008. Microbial flora drives interleukin 22 production in intestinal
NKp46+ cells that provide innate mucosal immune defense.
Immunity 29:958.
34 Takatori, H., Kanno, Y., Watford, W. T. et al. 2009. Lymphoid tissue
inducer-like cells are an innate source of IL-17 and IL-22. J. Exp.
Med. 206:35.
35 Sanos, S. L., Bui, V. L., Mortha, A. et al. 2009. RORgammat and
commensal microflora are required for the differentiation of
mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol.
10:83.
36 Satoh-Takayama, N., Lesjean-Pottier, S., Vieira, P. et al. 2010. IL-7
and IL-15 independently program the differentiation of intestinal
CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp.
Med. 207:273.
37 Aliahmad, P., de la Torre, B. and Kaye, J. 2010. Shared
dependence on the DNA-binding factor TOX for the development
of lymphoid tissue-inducer cell and NK cell lineages. Nat.
Immunol. 11:945.
38 Gascoyne, D. M., Long, E., Veiga-Fernandes, H. et al. 2009. The
basic leucine zipper transcription factor E4BP4 is essential for
natural killer cell development. Nat. Immunol. 10:1118.
39 Kamizono, S., Duncan, G. S., Seidel, M. G. et al. 2009. Nfil3/
E4bp4 is required for the development and maturation of NK cells
in vivo. J. Exp. Med. 206:2977.
40 Sawa, S., Cherrier, M., Lochner, M. et al. 2010. Lineage relationship analysis of ROR{gamma}t+ innate lymphoid cells. Science
330:594.
41 Luci, C., Reynders, A., Ivanov, I. I. et al. 2009. Influence of the
transcription factor RORgammat on the development of NKp46+
cell populations in gut and skin. Nat. Immunol. 10:75.
42 Van Maele, L., Carnoy, C., Cayet, D. et al. 2010. TLR5 signaling
stimulates the innate production of IL-17 and IL-22 by
CD3(neg)CD127+ immune cells in spleen and mucosa. J. Immunol.
185:1177.
43 Wolk, K., Witte, E., Wallace, E. et al. 2006. IL-22 regulates the
expression of genes responsible for antimicrobial defense,
cellular differentiation, and mobility in keratinocytes: a potential
role in psoriasis. Eur. J. Immunol. 36:1309.
44 Andoh, A., Zhang, Z., Inatomi, O. et al. 2005. Interleukin-22,
a member of the IL-10 subfamily, induces inflammatory responses
in colonic subepithelial myofibroblasts. Gastroenterology 129:969.
163
45 Ikeuchi, H., Kuroiwa, T., Hiramatsu, N. et al. 2005. Expression of
interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52:1037.
46 Wolk, K., Haugen, H. S., Xu, W. et al. 2009. IL-22 and IL-20 are key
mediators of the epidermal alterations in psoriasis while IL-17 and
IFN-gamma are not. J. Mol. Med. 87:523.
47 Ma, H. L., Liang, S., Li, J. et al. 2008. IL-22 is required for Th17
cell-mediated pathology in a mouse model of psoriasis-like skin
inflammation. J. Clin. Invest. 118:597.
48 Boniface, K., Bernard, F. X., Garcia, M., Gurney, A. L., Lecron, J.
C. and Morel, F. 2005. IL-22 inhibits epidermal differentiation and
induces proinflammatory gene expression and migration of
human keratinocytes. J. Immunol. 174:3695.
49 Geboes, L., Dumoutier, L., Kelchtermans, H. et al. 2009.
Proinflammatory role of the Th17 cytokine interleukin-22 in
collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum.
60:390.
50 Zenewicz, L. A., Yancopoulos, G. D., Valenzuela, D. M., Murphy,
A. J., Karow, M. and Flavell, R. A. 2007. Interleukin-22 but not
interleukin-17 provides protection to hepatocytes during acute
liver inflammation. Immunity 27:647.
51 Yang, L., Zhang, Y., Wang, L. et al. 2010. Amelioration of high fat
diet induced liver lipogenesis and hepatic steatosis by interleukin22. J. Hepatol. 53:339.
52 Ki, S. H., Park, O., Zheng, M. et al. 2010. Interleukin-22 treatment
ameliorates alcoholic liver injury in a murine model of chronicbinge ethanol feeding: role of signal transducer and activator of
transcription 3. Hepatology 52:1291.
53 Ren, X., Hu, B. and Colletti, L. M. 2010. IL-22 is involved in liver
regeneration after hepatectomy. Am. J. Physiol. Gastrointest. Liver
Physiol. 298:G74.
54 Silverberg, M. S., Cho, J. H., Rioux, J. D. et al. 2009. Ulcerative
colitis-risk loci on chromosomes 1p36 and 12q15 found by
genome-wide association study. Nat. Genet. 41:216.
55 Glocker, E. O., Kotlarz, D., Boztug, K. et al. 2009. Inflammatory
bowel disease and mutations affecting the interleukin-10 receptor.
N. Engl. J. Med. 361:2033.
56 Wilson, M. S., Feng, C. G., Barber, D. L. et al. 2010. Redundant
and pathogenic roles for IL-22 in mycobacterial, protozoan, and
helminth infections. J. Immunol. 184:4378.
57 Aujla, S. J., Chan, Y. R., Zheng, M. et al. 2008. IL-22 mediates
mucosal host defense against Gram-negative bacterial pneumonia. Nat. Med. 14:275.
58 Puel, A., Doffinger, R., Natividad, A. et al. 2010. Autoantibodies
against IL-17A, IL-17F, and IL-22 in patients with chronic
mucocutaneous candidiasis and autoimmune polyendocrine
syndrome type I. J. Exp. Med. 207:291.
59 Kagami, S., Rizzo, H. L., Kurtz, S. E., Miller, L. S. and Blauvelt, A.
2010. IL-23 and IL-17A, but not IL-12 and IL-22, are required for
optimal skin host defense against Candida albicans. J. Immunol.
185:5453.
60 De Luca, A., Zelante, T., D’Angelo, C. et al. 2010. IL-22 defines
a novel immune pathway of antifungal resistance. Mucosal
Immunol. 3:361.
61 Pickert, G., Neufert, C., Leppkes, M. et al. 2009. STAT3 links IL-22
signaling in intestinal epithelial cells to mucosal wound healing.
J. Exp. Med. 206:1465.