Interleukin-22, the Guardian of the Intestinal Stem Cell Niche?
Authors: Andreas Diefenbach
Journal: Immunity (2012)

Our molecular understanding of how immune cells protect epithelial cells against damage is limited. In this issue of Immunity, Hanash et al., 2012Hanash A.M. Dudakov J.A. Hua G. O'Connor M.H. Young L.F. Singer N.V. West M.L. Jenq R.R. Holland A.M. Kappel L.W. et al.Immunity. 2012; 37 (this issue): 339-350Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar report that interleukin-22 produced by innate lymphoid cells provides protection to the stem cell niche of the intestinal epithelium. Our molecular understanding of how immune cells protect epithelial cells against damage is limited. In this issue of Immunity, Hanash et al., 2012Hanash A.M. Dudakov J.A. Hua G. O'Connor M.H. Young L.F. Singer N.V. West M.L. Jenq R.R. Holland A.M. Kappel L.W. et al.Immunity. 2012; 37 (this issue): 339-350Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar report that interleukin-22 produced by innate lymphoid cells provides protection to the stem cell niche of the intestinal epithelium. Infections and infection-induced immunity are often associated with collateral damage to tissues, thereby necessitating tissue repair. At epithelial surfaces, tissue damage may occur frequently during steady state due to the continuous presence of bacteria and noxious compounds. Therefore, it has been proposed that immune cells contribute to the protection of epithelial surfaces by releasing factors that fortify the epithelial barrier and promote tissue repair. However, the cell types and molecular networks involved are poorly understood. It is widely believed that innate or innate-like lymphocytes at mucosal barriers may be central regulators of such processes. Lymphocytes located within the epithelium (intraepithelial lymphocytes [IELs]), in particular, the intestinal epithelium and the skin, were the first to be characterized as having a regulatory role (Jameson and Havran, 2007Jameson J. Havran W.L. Immunol. Rev. 2007; 215: 114-122Crossref PubMed Scopus (148) Google Scholar). For instance, IEL residing in the epidermis of the skin (i.e., dendritic epidermal γδ T cells) release growth factors (i.e., keratinocyte growth factor, insulin-like growth factor-1) involved in wound healing and tissue repair. Recently, additional subsets of innate lymphocytes have been discovered that are now widely referred to as innate lymphoid cells (ILCs) (Spits and Di Santo, 2011Spits H. Di Santo J.P. Nat. Immunol. 2011; 12: 21-27Crossref PubMed Scopus (650) Google Scholar). Numerous ILCs can be found at mucosal surfaces, and they have added an important facet to our understanding of how hematopoietic cells influence homeostasis and repair of epithelial and mesenchymal cell types (Sanos et al., 2011Sanos S.L. Vonarbourg C. Mortha A. Diefenbach A. Immunology. 2011; 132: 453-465Crossref PubMed Scopus (90) Google Scholar). For example, depletion of type 2 ILC (ILC2) in the context of influenza infection leads to a loss of airway epithelial integrity and impaired tissue remodeling (Monticelli et al., 2011Monticelli L.A. Sonnenberg G.F. Abt M.C. Alenghat T. Ziegler C.G. Doering T.A. Angelosanto J.M. Laidlaw B.J. Yang C.Y. Sathaliyawala T. et al.Nat. Immunol. 2011; 12: 1045-1054Crossref PubMed Scopus (1110) Google Scholar). The tissue-protective effect of ILC2 is at least in part mediated by their production of amphiregulin, a member of the epidermal growth factor family that promotes repair of epithelial cells. Another group of ILCs is developmentally dependent on the transcription factor RORγt, which they also continuously express (Spits and Di Santo, 2011Spits H. Di Santo J.P. Nat. Immunol. 2011; 12: 21-27Crossref PubMed Scopus (650) Google Scholar). They are now generally referred to as RORγt+ ILCs. Subsets of RORγt+ ILCs have lymphoid-tissue-inducing functions, and RORγt+ ILCs are strictly required for the formation of prenatally developing lymph nodes and Peyer's patches. They are also indispensible in the organogenesis of multiple postnatally forming cryptopatches and isolated intestinal lymphoid follicles (Eberl et al., 2004Eberl G. Marmon S. Sunshine M.J. Rennert P.D. Choi Y. Littman D.R. Nat. Immunol. 2004; 5: 64-73Crossref PubMed Scopus (796) Google Scholar). Each cryptopatch constitutes an accumulation of several hundred RORγt+ ILCs, and several thousand cryptopatches are found in the lamina propria of the small intestine directly underlying the intestinal crypts. RORγt+ ILCs embody an important source of various cytokines, in particular, the cytokine interleukin-22 (IL-22) (Spits and Di Santo, 2011Spits H. Di Santo J.P. Nat. Immunol. 2011; 12: 21-27Crossref PubMed Scopus (650) Google Scholar). IL-22 is unusual in that it acts mainly on epithelial cells and mesenchymal stroma cells, which express the IL-22 receptor. Thus, IL-22 signaling may constitute an important method by which immune cells control the function of epithelial cells. It was previously shown that mice genetically lacking IL-22 are more susceptible to dextrane sodium sulfate (DSS)-induced colitis (Sugimoto et al., 2008Sugimoto K. Ogawa A. Mizoguchi E. Shimomura Y. Andoh A. Bhan A.K. Blumberg R.S. Xavier R.J. Mizoguchi A. J. Clin. Invest. 2008; 118: 534-544PubMed Google Scholar). DSS is believed to damage the intestinal epithelium, causing severe inflammation. Neutralization of IL-22 had a profound impact on the restoration of tissue integrity, suggesting that IL-22 is important for the wound-healing response. Another line of evidence for the tissue-protective role of RORγt+ ILC-derived IL-22 comes from a thymic regeneration model. Following sublethal irradiation, IL-22-producing RORγt+ ILCs were required to protect medullary and cortical thymic epithelial cells (Dudakov et al., 2012Dudakov J.A. Hanash A.M. Jenq R.R. Young L.F. Ghosh A. Singer N.V. West M.L. Smith O.M. Holland A.M. Tsai J.J. et al.Science. 2012; 336: 91-95Crossref PubMed Scopus (272) Google Scholar). An important and largely unresolved question is which gene-expression networks in epithelial cells are controlled by IL-22. It has been shown that treatment of colonic explant cultures with IL-22 leads to the upregulation of a small family of antimicrobial lectin-like proteins (Reg3β and Reg3γ) and of other antimicrobial proteins (e.g., S100A8, S100A9, SAA3, and lactotransferrin) (Zheng et al., 2008Zheng Y. Valdez P.A. Danilenko D.M. Hu Y. Sa S.M. Gong Q. Abbas A.R. Modrusan Z. Ghilardi N. de Sauvage F.J. Ouyang W. Nat. Med. 2008; 14: 282-289Crossref PubMed Scopus (1446) Google Scholar). However, it remains unknown whether these genes are causally linked to the protection of epithelial cells or to the control of epithelial repair. It is intriguing that IL-22-producing RORγt+ ILCs reside in cryptopatches of the small intestine that directly underlie the crypts that contain stem cells and Paneth cells. Although Paneth cells are widely known to produce and secrete antimicrobial proteins, they have also recently been shown to provide niche support for a population of intestinal stem cells (also referred to as crypt-base columnar cells) that reside at the bottom of crypts, interspersed among the Paneth cells (Sato et al., 2011Sato T. van Es J.H. Snippert H.J. Stange D.E. Vries R.G. van den Born M. Barker N. Shroyer N.F. van de Wetering M. Clevers H. Nature. 2011; 469: 415-418Crossref PubMed Scopus (1723) Google Scholar). Paneth cells express the proteins EGF, TGF-α, Wnt3, and the Notch ligand Dll4, all of which are required for stem cell maintenance. Therefore, it has been hypothesized that RORγt+ ILCs control epithelial renewal and adaptation in response to damage by using IL-22 signaling to control the rate at which stem cells generate differentiating daughter cells (Sanos et al., 2011Sanos S.L. Vonarbourg C. Mortha A. Diefenbach A. Immunology. 2011; 132: 453-465Crossref PubMed Scopus (90) Google Scholar). The study in this issue of Immunity by Hanash et al., 2012Hanash A.M. Dudakov J.A. Hua G. O'Connor M.H. Young L.F. Singer N.V. West M.L. Jenq R.R. Holland A.M. Kappel L.W. et al.Immunity. 2012; 37 (this issue): 339-350Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar now provides evidence that both Paneth cells and stem cells express the IL-22 receptor and can, therefore, receive IL-22 signals. To investigate the protective effect of IL-22 on Paneth cells and stem cells, Hanash et al. analyzed stem cell and Paneth cell maintenance in a mouse model of graft-versus-host disease (GvHD). GvHD is a common and severe clinical complication of allogeneic bone marrow transplantation, during which graft-derived T cells attack allogeneic, radio-resistant cells of the host. The damage to host cells tends to be most pronounced at mucosal surfaces, such as those of the gastrointestinal tract. GvHD is considered to be a fundamental obstacle to the clinical success of bone marrow transplantation. Therefore, research into signals that may regulate the sensitivity of host cells to GvHD has wide ramifications and therapeutic implications. Hanash et al., 2012Hanash A.M. Dudakov J.A. Hua G. O'Connor M.H. Young L.F. Singer N.V. West M.L. Jenq R.R. Holland A.M. Kappel L.W. et al.Immunity. 2012; 37 (this issue): 339-350Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar show that neutralization of IL-22 leads to enhanced lethality in an experimental model of GvHD. Surprisingly, IL-22 deficiency in donor-derived cells had no or only minimal effects on the survival from GvHD, whereas IL-22 deficiency in the lethally irradiated recipient mice led to accelerated mortality and aggravated GvHD pathology. These data indicated that a radiation-resistant population of cells, subsequently identified as RORγt+ ILCs, is an important source of IL-22. Following lethal irradiation and bone marrow transplantation in the absence of allo-reactive T cells, RORγt+ ILCs did not decline for many days, and even after 3 months, in contrast to T lymphocytes, the majority of RORγt+ ILCs remained host derived. These data demonstrate that RORγt+ ILCs are maintained after lethal irradiation. Although IL-22-deficient mice showed increased mortality from GvHD, there were no differences in inflammation-related parameters. This raised the possibility that the aggravated clinical course was due to increased damage to epithelial cells. To this end, the authors used a reporter mouse to directly visualize stem cells. They show that stem cells were decreased following GvHD, probably due to attack by allo-reactive T cells. Importantly, IL-22-deficient mice showed an even more dramatic reduction of stem cells due to an increased rate of apoptosis when stem cells were deprived of IL-22 signals. Collectively, the data demonstrate for the first time that IL-22 produced by RORγt+ ILCs introduces changes in either stem cells themselves or in their niche cells that protect them against damage, such as that occurring in the context of lethal GvHD (Figure 1). The above finding represents an important starting point in addressing several crucial and outstanding questions. It remains to be shown which IL-22-controlled genes are involved in maintaining epithelial integrity and in protecting stem cells against damage. The Reg3 family of genes is certainly under the control of IL-22 (Sanos et al., 2011Sanos S.L. Vonarbourg C. Mortha A. Diefenbach A. Immunology. 2011; 132: 453-465Crossref PubMed Scopus (90) Google Scholar). Furthermore, IL-22-deficient mice suffering from GvHD have reduced epithelial-barrier function. However, it is not yet clear whether these antimicrobial lectins can directly influence stem cell survival. In addition, although Reg3 proteins are expressed by Paneth cells, they are unlikely to be found in stem cells. Thus, if Reg3 proteins are involved in the protection of intestinal stem cells, they act in a stem cell-extrinsic fashion. In future work, the gene-expression patterns of stem cells in the presence and absence of RORγt+ ILCs or IL-22 need to be analyzed for identification of candidate genes that directly affect their maintenance and susceptibility to damage. It is intriguing that Hanash et al., 2012Hanash A.M. Dudakov J.A. Hua G. O'Connor M.H. Young L.F. Singer N.V. West M.L. Jenq R.R. Holland A.M. Kappel L.W. et al.Immunity. 2012; 37 (this issue): 339-350Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar have identified IL-22 as having a strong effect on the gene-expression pattern of Paneth cells, because these cells have recently been identified as the intestinal stem cell niche (Sato et al., 2011Sato T. van Es J.H. Snippert H.J. Stange D.E. Vries R.G. van den Born M. Barker N. Shroyer N.F. van de Wetering M. Clevers H. Nature. 2011; 469: 415-418Crossref PubMed Scopus (1723) Google Scholar). Stem cell niches provide tunable signals that adjust stem cell differentiation and renewal to maintain organ homeostasis and function. Niche signals are provided in the form of adjustable molecular gradients of a few central signaling pathways, including Wnt, Bmp, and Fgf. How these gradients may be further shaped by environmental signals, specifically those from hematopoietic cells, is currently unknown. It will be an important line of future research to probe whether niche signals are modified by signals from ILC. Such future studies have the potential to unravel new molecular pathways by which immune cells regulate stem cell differentiation and renewal, thereby securing organ homeostasis and function. This has obvious therapeutic ramifications for GvHD and also for inflammatory bowel diseases and mucosal infections. Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host DiseaseHanash et al.ImmunityAugust 24, 2012In BriefLittle is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Full-Text PDF Open Archive