[Show abstract][Hide abstract] ABSTRACT: Basophils are, together with mast cells, typical innate effector cells of allergen-induced IgE-dependent allergic diseases. Both cell types express the high-affinity receptor for IgE (FcεR1), release histamine, inflammatory mediators, and cytokines following FcεR1 cross-linking. Basophils are rare granulocytes in blood, lymphoid, and non-lymphoid tissues, and the difficulties to detect and isolate these cells has hampered the study of their biology and the understanding of their possible role in pathology. Furthermore, the existence of other FcεR1-expressing cells, including professional Ag-presenting dendritic cells, generated some controversy regarding the ability of basophils to express MHC Class II molecules, present Ag and drive naïve T cell differentiation into Th2 cells. The focus of this review is to present the recent advances on the interactions between basophils and peripheral blood and tissue memory Th1, Th2, and Th17 cells, as well as their potential role in IgE-independent non-allergic chronic inflammatory disorders, including human inflammatory bowel diseases. Basophils interactions with the innate players of IgE-dependent allergic inflammation, particularly innate lymphoid cells, will also be considered. The previously unrecognized function for basophils in skewing adaptive immune responses opens novel perspectives for the understanding of their contribution to the pathogenesis of inflammatory diseases.
Frontiers in Immunology 08/2015; 6:399. DOI:10.3389/fimmu.2015.00399
[Show abstract][Hide abstract] ABSTRACT: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides.
In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease.
Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL.
PLoS Medicine 03/2015; 12(3):e1001796. DOI:10.1371/journal.pmed.1001796 · 14.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The soluble form of the transmembrane glycoprotein CD23 corresponding to the low-affinity receptor for the immunoglobulin E (sCD23) is found in the serum of patients with chronic lymphocytic leukemia (CLL). In this disease, an increase in sCD23 level is predictive of poor prognosis at diagnosis as well as during clinical outcome. Quantification of sCD23 is classically performed by ELISA assay, a method not routinely used in hematology laboratories. Our aim was to apply cytometric bead array (CBA) technology to measure sCD23 levels. We tested 420 serum samples, 360 from patients and 60 from healthy volunteers. We selected 3 pairs of monoclonal antibodies (moAb) recognizing the CD23 molecule that were tested in various conditions of temperature, centrifugation, washing or chemical supplementation. Satisfactory performances in terms of repeatability (CV: 5%) and reproducibility (CV: 6%) were obtained with the selected pair of antibodies, with a threshold of positivity at 6 ng/mL. CBA and ELISA techniques were correlated with a Spearman coefficient at 0.99. The reproducibility and reliability of the sCD23 CBA assay were confirmed, with a Spearman coefficient at 0.99 in a series of 23 CLL patients and 13 controls tested in 2 laboratories equipped with different cytometers and using different lots of CBA reagents. Data obtained with serum and plasma samples were correlated with a Spearman coefficient at 0.99. Our study validates a simple method that allows the clinicians to benefit from an indicator of prognosis at the diagnosis as well as a marker of the evolution of CLL disease.
Cytometry Part B Clinical Cytometry 10/2013; 86(2). DOI:10.1002/cytob.21135 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD.
Journal of Experimental Medicine 05/2013; 210(6). DOI:10.1084/jem.20122037 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Although the contribution of basophils as inducers or amplifiers of Th2 responses is still debated, prolonged basophil/CD4 T cell interactions were observed in lungs but not lymph nodes (LNs) of parasite-infected mice. However, the impact of basophils on the function of tissue CD4 effector T cells remains unknown.
Basophils were purified from the lungs of ovalbumin (OVA)-sensitized and OVA-challenged (OVA-immunized) mice or human peripheral blood for in vivo and in vitro functional studies. Pulmonary basophils were adoptively transferred to OVA-sensitized hosts to assess airway inflammation in bronchoalveolar lavage fluid (BALF) and Th2 responses in lung explants and draining LNs. Basophils were co-cultured with effector T cells or Ag-specific naïve T cells alone or in combination with dendritic cells (DCs); IL-4 production was determined by flow cytometry and ELISA.
Basophils accumulated in lungs of OVA-immunized mice. Adoptive transfer of basophils to OVA-sensitized hosts enhanced lung IL-4 and IL-13 release while co-administration of OVA further aggravated airway inflammation and Th2 responses in LNs. Mechanistic in vitro studies revealed that pulmonary basophils interacted with lung CD4 effectors, in the absence of DCs, to increase T cell survival and Th2 cytokine expression at the single cell level but amplified OVA-loaded DC-driven Th2 differentiation. Finally, human basophils augmented in vitro IL-4 expression in effector memory CD4 T cells that include CRTH2(+) cells through IL-4 and TCR-independent pathways.
Basophils may worsen Th2 inflammatory disorders through direct interactions with pathogenic CD4 T cells as well as by enhancing DC-induced Th2 cell development.
[Show abstract][Hide abstract] ABSTRACT: Basophils are a rare population of granulocytes that have long been associated with IgE-mediated and Th2-associated allergic diseases. However, the role of basophils in Th17 and/or Th1 diseases has not been reported. Here, we first report that basophils can be detected in the mucosa of Th17-associated lung and inflammatory bowel diseases (IBD) and further show that they accumulated in inflamed colons containing large quantities of IL-33. We next demonstrate that circulating basophils increased memory Th17 responses. Accordingly, IL-3 or IL-33-activated basophils amplified IL-17 release in effector memory (T(EM)), central memory (T(CM)) as well as CCR6(+) CD4 T cells. More specifically, basophils promoted the emergence of IL-17(+)IFN-γ(-), IL-17(+)IFN-γ(+) but not IL-17(-)IFN-γ(+) CD4 T cells in T(EM) and T(CM). Mechanistic analysis revealed that the enhancing effect of IL-17 production by basophils in T(EM) involved the ERK1/2 signaling pathway, occurred in a contact-independent manner and was partially mediated by histamine via H(2) and H(4) histamine receptors. Collectively, our findings reveal a previously unappreciated function for basophils that augmented Th17 and Th17/Th1 cytokine expression in memory CD4 T cells. Because basophils accumulated in inflamed IBD tissues, we propose that these cells are key players in chronic inflammatory disorders beyond Th2.
[Show abstract][Hide abstract] ABSTRACT: How do effector CD4 T cells escape cell death during the contraction of the immune response (IR) remain largely unknown. CD47, through interactions with thrombospondin-1 (TSP-1) and SIRP-α, is implicated in cell death and phagocytosis of malignant cells. Here, we reported a reduction in SIRP-α-Fc binding to effector memory T cells (T(EM)) and in vitro TCR-activated human CD4 T cells that was linked to TSP-1/CD47-induced cell death. The reduced SIRP-α-Fc binding (CD47(low) status) was not detected when CD4 T cells were stained with two anti-CD47 mAbs, which recognize distinct epitopes. In contrast, increased SIRP-α-Fc binding (CD47(high) status) marked central memory T cells (T(CM)) as well as activated CD4 T cells exposed to IL-2, and correlated with resistance to TSP-1/CD47-mediated killing. Auto-aggressive CD4 effectors, which accumulated in lymph nodes and at mucosal sites of patients with Crohn's disease, displayed a CD47(high) status despite a high level of TSP-1 release in colonic tissues. In mice, CD47 (CD47(low) status) was required on antigen (Ag)-specific CD4 effectors for the contraction of the IR in vivo, as significantly lower numbers of Ag-specific CD47(+/+)CD4 T cells were recovered when compared to Ag-specific CD47(-/-) CD4 T cells. In conclusion, we demonstrate that a transient change in the status of CD47, i.e. from CD47(high) to CD47(low), on CD4 effectors regulates the decision-making process that leads to CD47-mediated cell death and contraction of the IR while maintenance of a CD47(high) status on tissue-destructive CD4 effectors prevents the resolution of the inflammatory response.
PLoS ONE 08/2012; 7(8):e41972. DOI:10.1371/journal.pone.0041972 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The low molecular weight compound VAF347, and its pro-drug version VAG539, interact with the transcription factor aryl hydrocarbon receptor (AhR) on monocytes to mediate its anti-inflammatory activity in vitro and in vivo. AhR is a crucial factor for IL-22 production, which regulates skin and gut homeostasis. Here we investigated whether VAF347 might control the differentiation of naïve T cells into IL-22-secreting cells and/or regulate IL-22 production by memory T cells. Human monocytes exposed to VAF347 differentiated into dendritic cells capable of instructing a naïve CD4(+) T cell differentiation program that promoted IL-22 secretion and concomitantly inhibited IL-17 production. Whilst AhR ligation by VAF347 on naïve CD4(+) T cells favored the development of single IL-22-secreting cells (Th22), it suppressed the generation of T cells secreting either IL-22 and IFN-γ or IL-17 and IFN-γ. In contrast, memory T cells were refractory to AhR regulation since VAF347, AhR antagonist or AhR gene silencing did not modulate the production of any of these cytokines. Interfering with AhR functions using VAF347 may provide an efficient way to intervene with autoimmune disease since it would enhance the host protective function mediated by IL-22 while preventing the development of Th cells secreting pro-inflammatory cytokines.
Human immunology 05/2012; 73(8):795-800. DOI:10.1016/j.humimm.2012.05.002 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: T cell memory is the hallmark of adaptive immunity. Central questions are to determine which cells among proliferating effector T cells will live beyond the crash of the immune response (IR) and develop into functional memory T cells. CD47, considered as a marker of self, is implicated in cell death, cell elimination, and in the inflammatory response. We report in this article that CD47 expression was transiently regulated on Ag-specific CD4 T cells, that is, from CD47(high) to CD47(low) to CD47(high), during the course of the in vivo IR. Specifically, CD47(high) status marked central memory CD4 T cell precursors at an early time point of the IR. By contrast, cytokine production was a functional attribute restricted to CD47(high), but not CD47(low), polyclonal effector CD4 T cells during recall responses in an experimental model of chronic airway inflammatory disease. Passive transfer of CD47(high), but not CD47(low), CD4 T cells in nonlymphopenic naive mice generated long-lived memory T cells capable of anamnestic responses. We conclude that CD47(high) status on CD4 T cells identifies functional long-lived memory T cell progenitors.
The Journal of Immunology 03/2012; 188(9):4249-55. DOI:10.4049/jimmunol.1102702 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activation of microglia is regulated by controlling both its population size (through modulation of proliferation/death) and the production of inflammatory mediators. Retinoids control cellular proliferation, differentiation, and death. Natural retinoids have been shown to exhibit anti-inflammatory actions against activated microglia. However, the synthetic forms, which are regarded to be more stable in their actions, have not been explored for their capacity to modulate microglial activation, proliferation, and/or trigger cell death. The aim of the current study was to address these issues by using a model, lipopolysaccharide (LPS)-activated primary cultures of rat microglia, and the stable synthetic retinoid, 6-[3-adamantyl-4-hydroxyphenyl]-2-napthalene carboxylic acid (AHPN). Morphological observations of cluster of differentiation (CD) 11b (CD11b)-positive cells suggested that low concentration of AHPN (i.e. 5 μM) reduced LPS (1 μg/ml, 24 h)-activated morphology of microglia possibly toward a lower activated state, while attenuating nitrite production and the level of its synthesizing enzyme, inducible nitric oxide synthase (iNOS), as well as the chemokine, monocyte chemotactic protein-1 (MCP-1). The mechanisms behind these anti-inflammatory actions likely involved decreased activation of nuclear factor kappa B (NF-κB) as shown by the attenuated phosphorylation of its p65 subunit. In addition, fluorescence-activated cell sorting revealed that AHPN reduced the immunophenotypic marker of activation, CD68. LPS-mediated increase in cell number was reduced by low concentration AHPN, which resulted from inhibition of proliferation, based on decreased labeling for Ki-67 and reduced protein expression of cyclin D1, and not cell death. Higher concentrations of AHPN (50-100 μM) attenuated activation and cell number; however, the release of lactate dehydrogenase and appearance of annexin V and propidium iodide-positive cells suggested that cell death was its primary cause for reduced microglial activity. Overall, the current study shows that synthetic retinoids, such as AHPN, at low concentration attenuate microglial activation-associated responses, possibly via the inhibition of their cell proliferation without triggering cell death.
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) are crucial to shape the adaptive immune response. Extensive in vitro manipulation reprograms T(H)2 and T(H)17 cell lines into T(H)1 cells, leading to the concept of CD4(+) T(H) cell subset plasticity. The conversion of memory T(H)17 cells into T(H)2 cells or vice versa remains to be clarified.
We examined the localization of T(H)17/T(H)2 cells in vivo, their cellular origin (T(H)2 vs T(H)17), and the underlying mechanisms that drive the generation of these double T(H) producers.
Antigen-loaded bone marrow-derived DCs (ovalbumin-DCs) were repeatedly administered locally (intratracheally) or systemically (intravenously) to naive mice to elicit chronic airway inflammation. Inflamed lungs and mediastinal lymph nodes were examined for the presence of IL-17(+)IL-13(+)IL-4(+)CD4(+) T cells that coexpressed retinoic acid receptor-related orphan receptor γt and GATA-3 (T(H)17/T(H)2).
We show that repetitive administration of inflammatory ovalbumin-DCs, locally or systemically, promoted the development of antigen-specific T(H)17/T(H)2 cells in lungs and mediastinal lymph nodes. Immunized mice had IgE-independent and steroid-resistant airway inflammation with a mixed neutrophil and eosinophil infiltration of the bronchoalveolar lavage fluid. Airway inflammatory signal regulatory protein α-positive DCs reprogrammed in vitro-generated T(H)17 but not T(H)2 cells, as well as lung effector T(H) cells, into T(H)17/T(H)2 cells.
We demonstrate the existence of T(H)17/T(H)2 cells that express GATA-3 in inflamed tissues and their T(H)17 origin. We further propose that repeated immunization with inflammatory DCs prevails on the route of DC administration to drive T(H)17/T(H)2-associated chronic lung inflammation.
The Journal of allergy and clinical immunology 05/2011; 128(1):192-201.e6. DOI:10.1016/j.jaci.2011.04.029 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The interplay between innate and adaptive immune responses is essential for the establishment of allergic diseases. CD47 and its receptor, signal regulatory protein α (SIRP-α), govern innate cell trafficking. We previously reported that administration of CD47(+/+) but not CD47(-/-) SIRP-α(+) BM-derived DC (BMDC) induced airway inflammation and Th2 responses in otherwise resistant CD47-deficient mice. We show here that early administration of a CD47-Fc fusion molecule suppressed the accumulation of SIRP-α(+) DC in mediastinal LN, the development of systemic and local Th2 responses as well as airway inflammation in sensitized and challenged BALB/c mice. Mechanistic studies highlighted that SIRP-α ligation by CD47-Fc on BMDC did not impair Ag uptake, Ag presentation and Ag-specific DO11.10 Tg Th2 priming and effector function in vitro, whereas in vivo administration of CD47-Fc or CD47-Fc-pretreated BMDC inhibited Tg T-cell proliferation, pinpointing that altered DC trafficking accounts for defective Th priming. We conclude that the CD47/SIRP-α axis may be harnessed in vivo to suppress airway SIRP-α(+) DC homing to mediastinal LN, Th2 responses and allergic airway inflammation.
European Journal of Immunology 12/2010; 40(12):3510-8. DOI:10.1002/eji.201040797 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The balance between effector CD4(+) T cells secreting IL-17 (T(h)17) and regulatory T cells (Treg) plays an important role in autoimmune disorders that include rheumatoid arthritis (RA) and Crohn's disease. Tumor necrosis factor (TNF)-alpha is a key pro-inflammatory cytokine that contributes to disease pathogenesis. We investigated the interplay between CD45RA(+) Treg and TNF-alpha in the regulation of human T(h)17 differentiation. We found that CD45RA(+) Treg promoted while TNF-alpha inhibited naive CD4(+) T-cell differentiation into IL-17 and CCL20 co-expressing T(h)17 cells without influencing their IL-22 release. Unexpectedly, CD45RA(+) Treg depletion abrogated TNF-alpha suppressive function. Finally, dendritic cell-derived TNF-alpha suppressed the development of IL-17(+)CCL20(+) expressing T(h)17 cells. In conclusion, CD45RA(+) Treg positively governs human T(h)17 development, which is impaired by TNF-alpha. We propose that TNF-alpha may represent a negative feedback mechanism to control IL-17/CCL20- but not IL-22-associated autoimmune pathologies.
International Immunology 02/2010; 22(4):237-44. DOI:10.1093/intimm/dxp130 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Enteric infections remain a major health problem causing millions of deaths in developing countries. The interplay among the host intestinal epithelium, the mucosa-associated immune system and microbiota performs an essential role in gut homeostasis and protection against infectious diseases. Dendritic cells (DCs) play a key role in orchestrating protective immunity and tolerance in the gut. The mechanisms by which DCs adapt their responses and discriminate between virulent microbes and trillions of innocuous bacteria remain ill-defined. Here we investigated the effect of cross-talk between commensal-related bacteria (CB) and Toll-like receptor (TLR) agonists on DC activation and the outcome of the in vitro T helper response. Human monocyte-derived DCs were exposed to eight different Gram-positive or Gram-negative CB strains prior to activation with five different TLR agonists. The key polarizing cytokines interleukin (IL)-12p70, IL-10, IL-1beta and IL-6 were quantified and the fate of naïve T-cell differentiation was evaluated. We identified a unique combination of Lactobacillus casei and TLR3 signals that acted in synergy to selectively increase IL-12p70 secretion. Exposure to poly(I:C) converted L. casei-treated DCs into potent promoters of T helper type 1 (Th1) responses. We propose that DCs can integrate harmless and dangerous non-self signals delivered by viral products, to mount robust Th1 responses. Thus, in vivo DC targeting with selective probiotics may improve strategies for the management of enteric diseases.
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) are essential for the initiation and maintenance of T(H)2 responses to inhaled antigen that lead to the establishment of allergic diseases. Two subpopulations of nonplasmacytoid DCs (ie, CD11b(low)CD103+ and CD11b(high)CD103(-)) are found in lung/airway tissues. Yet the identification and migratory properties of the DC subset that contributes to T(H)2-mediated responses remain to be clarified. CD47, a signal regulatory protein (SIRP)-alpha partner, reportedly governed skin DC migration.
We here thought to investigate the role of CD47/SIRP-alpha interactions in airway DC trafficking and the development of allergic airway inflammation.
We characterized the DC influx into lungs and mediastinal lymph nodes in CD47(-/-) and CD47(+/+) BALB/c mice by using experimental models of allergic asthma. Mice were systemically (intraperitoneal ovalbumin/alum) or locally (intratracheal ovalbumin-loaded bone marrow-derived DCs) immunized and challenged by ovalbumin aerosol. We also evaluated the consequences of SIRP-alpha-Fc fusion molecule administration on the induction of airway disease in BALB/c mice.
SIRP-alpha selectively identified the CD11b(high)CD103(-) DC subset that predominantly accumulated in mediastinal lymph nodes during airway inflammation. However, CD103(-)SIRP-alpha+ DC trafficking, T(H)2 responses, and airway disease were impaired in CD47(-/-) mice. Importantly, the adoptive transfer of CD103(-) SIRP-alpha+CD47(+/+) but not CD47(-/-) DCs elicited a strong T(H)2 response in CD47(-/-) mice. Finally, the administration of SIRP-alpha-Fc molecule protected BALB/c mice from allergic airway inflammation.
Lung CD11b(high)CD103(-)SIRP-alpha+ DC migration is governed by self-CD47 expression, and manipulation of the CD47/SIRP-alpha pathway suppresses CD103(-)SIRP-alpha(+) DC-driven pathogenic T(H)2 responses and airway inflammation.
The Journal of allergy and clinical immunology 09/2009; 124(6):1333-42.e1. DOI:10.1016/j.jaci.2009.07.021 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mesenteric lymph node (mLN) CD103 (alphaE integrin)(+) dendritic cells (DCs) induce regulatory T cells and gut tolerance. However, the function of intestinal CD103(-) DCs remains to be clarified. CD47 is the ligand of signal regulatory protein alpha (SIRPalpha) and promotes SIRPalpha(+) myeloid cell migration. We first show that mucosal CD103(-) DCs selectively express SIRPalpha and that their frequency was augmented in the lamina propria and mLNs of mice that developed Th17-biased colitis in response to trinitrobenzene sulfonic acid. In contrast, the percentage of SIRPalpha(+)CD103(-) DCs and Th17 responses were decreased in CD47-deficient (CD47 knockout [KO]) mice, which remained protected from colitis. We next demonstrate that transferring wild-type (WT), but not CD47 KO, SIRPalpha(+)CD103(-) DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRPalpha(+)CD103(-) DCs for efficient trafficking to mLNs in vivo, whereas it was dispensable on both DCs and T cells for Th17 polarization in vitro. Finally, administration of a CD47-Fc molecule resulted in reduced SIRPalpha(+)CD103(-) DC-mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRPalpha(+)CD103(-) DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47-SIRPalpha axis as a potential therapeutic target for inflammatory bowel disease.
Journal of Experimental Medicine 09/2009; 206(9):1995-2011. DOI:10.1084/jem.20082805 · 12.52 Impact Factor