Before They Were Gut Dendritic Cells
2009; Cell Press; Volume: 31; Issue: 3 Linguagem: Inglês
10.1016/j.immuni.2009.08.015
ISSN1097-4180
Autores Tópico(s)T-cell and B-cell Immunology
ResumoGut lamina propria dendritic cell (DC) subsets have specialized functions. In this issue of Immunity, Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar and Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar describe the different blood precursors for CD103+ and CD103− DC subsets. Gut lamina propria dendritic cell (DC) subsets have specialized functions. In this issue of Immunity, Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar and Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar describe the different blood precursors for CD103+ and CD103− DC subsets. How the intestine can tolerate trillions of intestinal bacteria, initiate tolerance toward food antigens, and fight infections is the subject of an intense area of research. Recent advances have highlighted a fundamental role of dendritic cells (DCs) in these functions. In the mouse lamina propria (LP), DCs are characterized by the high expression of CD11c and can be distinguished based on the expression of the integrin CD103, which recognizes E-cadherin. CD103+ DCs can drive the differentiation of T regulatory (Treg) cells, the effectors of tolerance, via a mechanism that is mediated by retinoic acid (RA) and TGF-β (Sun et al., 2007Sun C.M. Hall J.A. Blank R.B. Bouladoux N. Oukka M. Mora J.R. Belkaid Y. J. Exp. Med. 2007; 204: 1775-1785Crossref PubMed Scopus (1500) Google Scholar). In contrast, CD103− DCs can be subdivided into two subsets. One subset expresses CX3CR1 and drives the development of T helper 17 (Th17) cells (Atarashi et al., 2008Atarashi K. Nishimura J. Shima T. Umesaki Y. Yamamoto M. Onoue M. Yagita H. Ishii N. Evans R. Honda K. Takeda K. Nature. 2008; 455: 808-812Crossref PubMed Scopus (844) Google Scholar). The other subset expresses the Toll-like receptor 5 (TLR5) and drives the differentiation of both Th17 cells and IgA class-switched B cells (Uematsu et al., 2008Uematsu S. Fujimoto K. Jang M.H. Yang B.G. Jung Y.J. Nishiyama M. Sato S. Tsujimura T. Yamamoto M. Yokota Y. et al.Nat. Immunol. 2008; 9: 769-776Crossref PubMed Scopus (592) Google Scholar). However, it was not clear whether these DCs represented different activation states of the same subset (expressing or not the CD103) or whether they represented two different subsets arising from distinct blood precursors. In this issue of Immunity, two independent reports by Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar and Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar describe that the CD103+ and CD103− DC subsets are further distinguishable based on the expression of CD11b and CX3CR1 and derive from different bone marrow precursors. By using very elegant model systems based on conditional ablation of DCs and engraftment with defined DC precursors, the two groups demonstrate that a common macrophage and DC precursor (MDP) can give rise to both CD103+ and CD103− DCs, whereas pre-DCs or monocytes can differentiate only into CD103+ or CD103− DCs, respectively (Figure 1). These studies also describe the different requirements of growth factors for the differentiation of the two major DC subsets. Both reports show a common requirement of Flt3L for the differentiation of CD11b+CD103+ and CD11b−CD103+ DCs whereas Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar show that GM-CSF seems to be more involved in the differentiation of CD11b+ (mostly CD103−) DCs. In contrast, Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar find that GM-CSFR expression is dispensable for CD103− DC differentiation, whereas it is required for the differentiation of CD11b+CD103+ and CD11b−CD103+ DCs. Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar also demonstrate a requirement of M-CSFR for the differentiation of the CD103− population. This apparent discrepancy may be due to the different way used by the two groups to phenotypically separate the two cell types. In both cases, the cells were separated based on the high expression of CD11c expression, but whereas Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar report that they separated the cells based on the expression of CD11b and CX3CR1, Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar report that they separated the DCs based on the expression of MHC class II and CD11b. In addition, as shown by Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar, different compartments of either the small or large intestine (i.e., the intestinal epithelial cell fraction, the LP, the serosa, or the muscolaris) yielded different DC populations, including a contaminating lymphoid population characterized by the expression of CD103 and the absence of CD11b. Hence, it is likely that the same progenitor may require different growth factors or combination of growth factors for their differentiation depending on the compartment that is analyzed. The different origin of the DC populations reflects differences in DC function. When the mesenteric lymph node (MLN) is analyzed, it is clear that again that the DC populations can be distinguished based on CD103 expression; however, whereas the CD103+ population expresses CCR7 and seems to be derived from a migratory LP CD103+ DC population, the CD103− DC population seems to be a resident nonmigratory cell type. Indeed, only 20% of MLN CD103− DCs express high CX3CR1, suggesting a different origin than LP CD103− DCs that uniformly express CX3CR1. This is an intriguing observation because it indicates that under steady-state condition, only CD103+ DCs can migrate into the MLN. This population is required for the differentiation of Treg cells (Coombes et al., 2007Coombes J.L. Siddiqui K.R. Arancibia-Carcamo C.V. Hall J. Sun C.M. Belkaid Y. Powrie F. J. Exp. Med. 2007; 204: 1757-1764Crossref PubMed Scopus (2166) Google Scholar), and therefore it could be involved in tolerance induction to food antigens. What was unexpected is that CD103+CX3CR1− DCs are also required for the initial transport of Salmonella from the intestine to the MLN (Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar). Indeed, it has been shown that DCs can extend protrusions across the epithelial barrier (Rescigno et al., 2001Rescigno M. Urbano M. Valzasina B. Francolini M. Rotta G. Bonasio R. Granucci F. Kraehenbuhl J.P. Ricciardi-Castagnoli P. Nat. Immunol. 2001; 2: 361-367Crossref PubMed Scopus (2025) Google Scholar), and CX3CR1 expression is required for DC extensions (Niess et al., 2005Niess J.H. Brand S. Gu X. Landsman L. Jung S. McCormick B.A. Vyas J.M. Boes M. Ploegh H.L. Fox J.G. et al.Science. 2005; 307: 254-258Crossref PubMed Scopus (1287) Google Scholar). Hence it would be more logical to think that CD103−CX3CR1+ DCs are the first to migrate to MLNs and to carry ingested microbes. In the model used by Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar, mice are treated with streptomycin and this facilitates Salmonella entrance across epithelial cells. Thus, it is likely that CD103+ DCs acquire Salmonella after their independent crossing across the epithelial barrier. However, it cannot be excluded that CD103+ DCs may also extend their protrusions across the epithelial barrier because we have observed that DC extensions in CX3CR1-GFP and MHC II-GFP mice are only partly overlapping (unpublished observations), suggesting that two populations of DCs may extend protrusions in the lumen. Alternatively, Salmonella may be transferred from CD103−CX3CR1+ DCs to CD103+CX3CR1− DCs but this has not been demonstrated. Regardless, it appears that CD103+ DCs may be the first cells migrating to the draining MLN both under steady-state and under infection conditions. It is not clear what is the function of these migrating CD103+ DCs carrying the Salmonella into the MLN given their propensity to drive Treg cell development (Coombes et al., 2007Coombes J.L. Siddiqui K.R. Arancibia-Carcamo C.V. Hall J. Sun C.M. Belkaid Y. Powrie F. J. Exp. Med. 2007; 204: 1757-1764Crossref PubMed Scopus (2166) Google Scholar). These cells could be exploited by Salmonella for its own spreading in the absence of productive immunity, but this remains to be established. Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar have instead focused on the role of monocyte-derived CD103−CX3CR1+ DCs. By conditionally ablating mice of DCs and reconstituting them with monocytes that give rise only to CD103−CX3CR1+ DCs, they have shown that these DCs are sufficient to restore the internalization of noninvasive Salmonella and to present orally administered antigens. However, it remains to be established what is the outcome of this presentation, in terms of T cell activation and polarization. Varol et al., 2009Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.-D. Shakhar G. Jung S. Immunity. 2009; 31 (this issue): 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar also show that when mice display only CD103−CX3CR1+ DCs, they are more susceptible to DSS-induced colitis. This may be the result of at least two non-mutually exclusive possible scenarios. The first is that CD103+ DCs are required to maintain tolerance in the gut because they drive the development of Treg cells that may be involved in preserving tissue integrity or limiting inflammatory damage. In the absence of CD103+ DCs, there may be a decrease in Treg cell differentiation and a concomitant increase in the development of colitogenic Th17 cells as indicated by the fact that CD103−CX3CR1+ DCs have been shown to drive Th17 cell development in the presence of bacteria-derived ATP (Atarashi et al., 2008Atarashi K. Nishimura J. Shima T. Umesaki Y. Yamamoto M. Onoue M. Yagita H. Ishii N. Evans R. Honda K. Takeda K. Nature. 2008; 455: 808-812Crossref PubMed Scopus (844) Google Scholar). Hence, the balance between CD103+ and CD103− DCs is required to preserve gut homeostasis. The second possibility may be the capacity of the local microenvironment to control DC function and to inhibit the development of inflammatory Th1 cell-type of responses (Iliev et al., 2009Iliev I.D. Mileti E. Matteoli G. Chieppa M. Rescigno M. Mucosal Immunol. 2009; 2: 340-350Crossref PubMed Scopus (282) Google Scholar). Indeed, resident LP DCs are unable to produce IL-12 and to drive Th1 cell-type of responses because they either lack TLR expression (except for TLR5) or they are unresponsive to TLR stimulation (Monteleone et al., 2008Monteleone I. Platt A.M. Jaensson E. Agace W.W. Mowat A.M. Eur. J. Immunol. 2008; 38: 1533-1547Crossref PubMed Scopus (84) Google Scholar). It is possible that CD103−CX3CR1+ DCs arising from the transferred monocytes may not have time to be conditioned by the local microenvironment in the absence of CD103+ DCs and become “inflammatory” leading to Th1 cell differentiation. Additional studies are required to address this issue. It remains to be understood whether monocytes are recruited at all during steady-state. Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar show that in the absence of DC ablation, monocytes are unable to repopulate the LP and to give rise to CD103− DCs. This could be due to the low turn-over of CD103− DCs in the LP because in mice connected by parabiosis, only the CD103+ population is replenished by parabiont-derived cells, whereas the CD103− population is not. Alternatively, it could be due to the proliferation of either the monocytes or the differentiated CD103− DCs directly in situ (Jaensson et al., 2008Jaensson E. Uronen-Hansson H. Pabst O. Eksteen B. Tian J. Coombes J.L. Berg P.L. Davidsson T. Powrie F. Johansson-Lindbom B. Agace W.W. J. Exp. Med. 2008; 205: 2139-2149Crossref PubMed Scopus (492) Google Scholar). In contrast, DC ablation could lead to the elimination of both cell types and to the need to reconstitute the DC pools by recruitment of blood precursors. What is the function of CX3CR1+ DCs? One possibility would be that they are responsible to confer an initial protection toward commensals and pathogenic microorganisms via the induction (or restimulation) of Th17 cells. Alternatively, these cells may migrate at later time points after infection and may be responsible for the initiation of Th17 cell differentiation in the draining lymph nodes. Another intriguing possibility is that CD103−CX3CR1+ DCs offer only an initial defense whereas the cells responsible for the initiation of a protective immune response toward Salmonella are inflammatory monocytes that are recruited after infection. These recruited monocytes may differentiate into an additional inflammatory type of DCs that can initiate Th1 cell immune responses to Salmonella. Another important question that arises from the present studies is whether the progenitor cells are intrinsically committed to become CD103+ or CD103− cells and to acquire their mucosal specialized functions or whether these characteristics are extrinsically conferred by the local microenvironment. It has been shown that it is possible to “condition” bone-marrow-derived DCs into the CD103+ phenotype of mucosal DCs. In particular, the direct interaction with epithelial cells drives the upregulation of CD103 whereas soluble factors released by epithelial cells, including RA and TGF-β, mediate the acquisition of tolerogenic properties (Figure 1; Iliev et al., 2009Iliev I.D. Mileti E. Matteoli G. Chieppa M. Rescigno M. Mucosal Immunol. 2009; 2: 340-350Crossref PubMed Scopus (282) Google Scholar). In this context, Bogunovic et al., 2009Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. et al.Immunity. 2009; 31 (this issue): 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar have shown that CD103+ DCs are often associated with epithelial cells. In contrast, it is possible that the phenotype of CX3CR1+ DCs is conferred directly by the luminal bacteria as indicated by the fact that bacteria-derived ATP is required to drive Th17-cell-inducing DCs (Atarashi et al., 2008Atarashi K. Nishimura J. Shima T. Umesaki Y. Yamamoto M. Onoue M. Yagita H. Ishii N. Evans R. Honda K. Takeda K. Nature. 2008; 455: 808-812Crossref PubMed Scopus (844) Google Scholar). Hence different environmental conditions may confer the properties to CD103+ and CD103− DCs. In conclusion, at least two different blood precursors differentiate into distinct LP DC subsets in response to specific growth factors. The challenge is to identify the molecular pathways of this differentiation and where it occurs. Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and FunctionsVarol et al.ImmunitySeptember 3, 2009In BriefThe intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. Full-Text PDF Open ArchiveOrigin of the Lamina Propria Dendritic Cell NetworkBogunovic et al.ImmunitySeptember 3, 2009In BriefCX3CR1+ and CD103+ dendritic cells (DCs) in intestinal lamina propria play a key role in mucosal immunity. However, the origin and the developmental pathways that regulate their differentiation in the lamina propria remain unclear. We showed that monocytes gave rise exclusively to CD103−CX3CR1+ lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (Flt3) ligands. In contrast, common DC progenitors (CDP) and pre-DCs, which give rise to lymphoid organ DCs but not to monocytes, differentiated exclusively into CD103+CX3CR1− lamina propria DCs under the control of Flt3 and granulocyte-macrophage-colony-stimulating factor receptor (GM-CSFR) ligands. Full-Text PDF Open Archive
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