Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

Varol, Chen; Vallon-Eberhard, Alexandra; Elinav, Eran; Aychek, Tegest; Shapira, Yami; Luche, Hervé; Fehling, Hans Jöerg; Hardt, Wolf‐Dietrich; Shakhar, Guy; Jung, Steffen

doi:10.1016/j.immuni.2009.06.025

Cited by 638 publications

(775 citation statements)

References 54 publications

Supporting

Mentioning

727

Contrasting

Unclassified

Order By: Relevance

“…The mutually exclusive expression of monocyte markers and Flt3 by CD103 À and CD103 1 DC, respectively, strongly suggests that the two DC subsets develop from different progenitors. Our data are in agreement with two recent studies showing that at the steadystate, LP CD103 1 CX 3 CR1 À/low DC arise from common DC progenitors and pre-DC without a monocytic intermediate through a Flt3 ligand-mediated pathway whereas CD103 À CX 3 CR1 1 DC derive from Ly6C hi monocytes [10,21]. In addition, our results indicate that the developmental distinction between CD103 1 and CD103 À DC in MLN is retained during intestinal inflammation.…”

Section: Discussionsupporting

confidence: 93%

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

View full text Add to dashboard Cite

Intestinal CD103 1 DC promote the differentiation of Foxp3 1 Treg from naïve CD4 1 T cells through mechanisms involving TGF-b and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103 1 DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103 1 DC, which is associated with lower expression of tgfb2 and aldh1a2. Accordingly, CD103 1 DC taken from colitic mice are impaired in their ability to induce Foxp3 1 Treg and instead favour the emergence of IFN-c-producing CD4 1 T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103 1 DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103 1 DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103 1 DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.Key words: Colitis . DC . Intestinal immunity . Ontogeny . Treg IntroductionThe intestinal immune system must maintain a fine balance between harmless responses to food and commensal bacteria and protective immunity to invading pathogens. It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known. One possibility is that these activities are mediated by distinct DC populations and indeed many subtypes of DC have been identified in the gut [4]. It has been proposed that resident gutconditioned DC may favour tolerogenic responses, whereas newly recruited inflammatory DC may drive host protective immunity.Alternatively, tissue-resident DC may adopt distinct functions under homeostatic and inflammatory conditions [4,5].We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10]. Under homeostatic conditions, CD103 1 DC in MLN promote the development of Foxp3 1 Treg. By contrast, the reciprocal CD103 À MLN DC population displays a more pro-inflammatory phenotype and appears to represent a developmentally distinct DC population [9].In intestinal inflammation, immune regulatory pathways that normally promote tolerance in the intestine break down. Whether this is attributable to changes in DC populations or their function in the MLN is not known. Here, we show that in colitic mice, the tolerogenic properties of CD103 1 MLN DC are lost and that this APC population now drives inflammatory T-cell responses that may c...

show abstract

Section: Discussionsupporting

confidence: 93%

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

View full text Add to dashboard Cite

show abstract

“…Our analysis of CD103 expression on T cells concludes that GM-CSF does not grossly affect the CD103 expression on T cells. Apart from T cells and resident CD8 1 DCs, certain mucosal DCs [31,32] and dermal DCs also express CD103 [33]. GM-CSF deficiency did not affect the numbers of resident CD8 1 DCs, but led to a severe reduction in the numbers of dermal CD103 1 DCs [33].…”

Section: Discussionmentioning

confidence: 99%

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

et al. 2011

View full text Add to dashboard Cite

Resident CD8 1 DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8 1 DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L. monocytogenes by resident CD8 1 DCs. This previously unrecognized functional enhancement of CD8 1 DCs by GM-CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM-CSF was also marked by CD103 expression on CD8 1 DCs that was strongly regulated by GM-CSF. Our findings not only identify GM-CSF as a key molecule regulating CD8 1 DC function, but also as a factor responsible for functional heterogeneity of CD8 1 DCs that is at least substantially demarcated by CD103 expression.Keywords: CD8 1 DC . CD103 . Cross-presentation . Granulocyte-macrophage colony-stimulating factor . Listeria monocytogenes Supporting Information available online IntroductionDCs found in the spleen can be grossly separated into CD8 1 DCs and CD8 À DCs. The latter includes CD8 À CD4 1 and CD8 À CD4 À conventional DCs and CD45RA 1 plasmacytoid DCs. Different DC subsets have different functions. Notably, the resident CD8 1 DCs show superior capacity for ingesting cell-associated antigens [1], for cross-presenting antigens (i.e. presenting exogenous antigens to CD8 1 T cells) [2][3][4], for the rapid uptake of certain bacterial pathogens [5] and for producing . It has been previously reported that a small proportion of CD8 1 DCs express the integrin CD103 and these CD103-expressing CD8 1 DCs are enriched in cells engulfing cellular antigens and cross-priming CD8 1 T cells [7]. However, it is unclear what regulates the above Ã Co-senior authors. Here, we investigated whether GM-CSF might influence the function of CD8 1 DCs and CD103 expression. Functionally, DCs from GM-CSF transgenic (GMtg) mice had enhanced crosspresentation, whereas in the absence of GM-CSF signaling, crosspresentation was reduced. Rapid uptake of Listeria monocytogenes by CD8 1 DCs was also reduced in the absence of GM-CSF. Phenotypically, we showed that bacterial infection preferentially increased CD103 expression by CD8 1 DCs and this increase was dependent on GM-CSF. Together, our results identify a critical role for GM-CSF in preferentially regulating expression of the integrin CD103 by CD8 1 DCs and in regulating certain functions of CD8 1 DCs. ResultsGM-CSF enhances cross-presentation by CD8 1 DCs GM-CSF is a cytokine that exists at very low levels at steady state but is greatly induced during infection and inflammation [13]. To understand the role of GM-CSF in regulating the functions of CD8 1 DCs, we chose mouse models with GM-CSF overexpression. We first compared the cross-presentation by CD8 1 DCs from GMtg mice and control littermates. When soluble OVA was used as the antigen in vitro, CD...

show abstract

“…[113][114][115], whereas relative levels of F4/80 and CD11b may discriminate between monocyte-derived macrophages and yolk sac-derived macrophages (such as Kupffer cells in liver, Langerhans' cells in skin or microglia in brain) [2]. For Mo-DC, markers for discrimination from other DC-subsets have been identified, such as DC-SIGN for DCs in inflamed lymph nodes [48], CX3CR1 for intestinal lamina propia DCs [52] and TNF-α/ROS-production for Tip-DCs [116,117] …”

Section: Development Of Monocytes In Cancermentioning

confidence: 99%

Monocytes and Macrophages in Cancer: Development and Functions

Richards

Hettinger

Feuerer

2012

Cancer Microenvironment

171

122

View full text Add to dashboard Cite

Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages, a very heterogeneous cell population in terms of phenotype and pro-tumor function, supporting tumor initiation, local progression and distant metastasis. Therefore, targeting monocytes and macrophages is a promising immunotherapeutic approach. This review will focus on the development of monocytes as macrophage precursors, the functions of tumorassociated macrophages and the possibility of interfering with tumor development and progression by targeting these myeloid cells.

show abstract

Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

Cited by 638 publications

References 54 publications

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

Monocytes and Macrophages in Cancer: Development and Functions

Contact Info

Product

Resources

About

Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

Cited by 638 publications

References 54 publications

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8+ spleen dendritic cells

Monocytes and Macrophages in Cancer: Development and Functions

Contact Info

Product

Resources

About

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells