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Mesenteric lymph node (mLN) CD103 (αE 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 α (SIRPα) and promotes SIRPα+ myeloid cell migration. We first show that mucosal CD103− DCs selectively express SIRPα 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 SIRPα+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, SIRPα+CD103− DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRPα+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 SIRPα+CD103− DC–mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRPα+CD103− DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47–SIRPα axis as a potential therapeutic target for inflammatory bowel disease.

The past decades have been marked by spectacular progress towards understanding how dendritic cells (DCs) interact with T cells to elicit protective immune responses to fight infectious diseases and cancer. DCs that are lying at the interface between innate and adaptive immunity, are educated in peripheral tissues prior to their journey to the secondary lymphoid organs (SLO) whereby they dictate different classes of T cell responses. Uncontrolled or unwanted inflammatory responses are the price to pay to eliminate pathogens. However, if not self-limited, they may induce collateral damages that result in chronic inflammation often associated with autoimmune disorders. CD47 and its two ligands, i.e. thrombospondin 1 (TSP-1) and SIRP-alpha, were identified as a previously unappreciated inhibitory axis of DC and T cell functions. TSP-1 is predominantly a negative regulator of DC and T cell function while basal SIRP-alpha ligation on APC by CD47 enforces tolerance. Yet, CD47/SIRP-alpha interaction positively controls DC and innate cell transendothelial migration. Due to the promiscuity of the protein interactions for CD47 and its ligands, it is quite interesting to note that deletion of the CD47 gene in mice largely agrees with the in vitro data with human cells. In fact, the well-conserved tissue distribution of CD47 and SIRP-alpha across species may facilitate the transition from bench to bedside. We thus propose CD47/TSP-1/SIRP-alpha axis as an important sensor to maintain homeostasis and regulate innate and adaptive immune responses.

Peripheral CD103+Foxp3+ regulatory T cells (Tregs) can develop both from conventional naive T cells upon cognate Ag delivery under tolerogenic conditions and from thymic-derived, expanded/differentiated natural Tregs. We here show that CD47 expression, a marker of self on hematopoietic cells, selectively regulated CD103+Foxp3+ Treg homeostasis at the steady state. First, the proportion of effector/memory-like (CD44highCD62Llow) CD103+Foxp3+ Tregs rapidly augmented with age in CD47-deficient mice (CD47−/−) as compared with age-matched control littermates. Yet, the percentage of quiescent (CD44lowCD62Lhigh) CD103−Foxp3+ Tregs remained stable. Second, the increased proliferation rate (BrdU incorporation) observed within the CD47−/−Foxp3+ Treg subpopulation was restricted to those Tregs expressing CD103. Third, CD47−/− Tregs maintained a normal suppressive function in vitro and in vivo and their increased proportion in old mice led to a decline of Ag-specific T cell responses. Thus, sustained CD47 expression throughout life is critical to avoid an excessive expansion of CD103+ Tregs that may overwhelmingly inhibit Ag-specific T cell responses.

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 CD47high to CD47low to CD47high, during the course of the in vivo IR. Specifically, CD47high 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 CD47high, but not CD47low, polyclonal effector CD4 T cells during recall responses in an experimental model of chronic airway inflammatory disease. Passive transfer of CD47high, but not CD47low, CD4 T cells in nonlymphopenic naive mice generated long-lived memory T cells capable of anamnestic responses. We conclude that CD47high status on CD4 T cells identifies functional long-lived memory T cell progenitors.

No abstract

The impairments of protective mucosal immunity which cause susceptibility to oropharyngeal candidiasis (OPC) in HIV infection remain undefined. This study used a model of OPC in CD4C/HIV MutA transgenic (Tg) mice expressing Rev, Env, and Nef of HIV-1 to investigate the role of transgene expressing dendritic cells (DCs) and CD4+ T cells in maintenance of chronic oral carriage of Candida albicans. DCs were depleted in the Tg mice and had an immature phenotype, with low expression of MHC class II and IL-12. CD4+ T cells were quantitatively reduced in the oral mucosa, cervical lymph nodes (CLNs) and peripheral blood of the Tg mice, and displayed a polarization toward a nonprotective Th2 response. Proliferation of CLN CD4+ T cells from infected Tg mice in response to C. albicans Ag in vitro was abrogated and the cells failed to acquire an effector phenotype. Coculture of C. albicans-pulsed DCs with CD4+ T cells in vitro showed that Tg expression in either or both of these cell populations sharply reduced the proliferation of CD4+ T cells and their production of IL-2. Finally, transfer of naive non-Tg CD4+ T cells into these Tg mice restored proliferation to C. albicans Ag and sharply reduced oral burdens of C. albicans. Overall, these results indicate that defective CD4+ T cells primarily determine the susceptibility to chronic carriage of C. albicans in these Tg mice.

The interplay between innate and adaptive immune responses is essential for the establishment of allergic diseases. CD47 and its receptor, signal regulatory protein a (SIRP-a), govern innate cell trafficking. We previously reported that administration of CD47 1/1 but not CD47 À/À SIRP-a 1 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-a 1 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-a 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-a axis may be harnessed in vivo to suppress airway SIRP-a 1 DC homing to mediastinal LN, Th2 responses and allergic airway inflammation.Key words: Airway inflammation . CD47 . DC . Signal regulatory protein a . Th2Supporting Information available online IntroductionAllergic disorders result from aberrant Th2 responses to common environmental Ag [1]. Allergic asthma is characterized by increased IgE production and the accumulation of Th2 effector/ memory cells in the bronchial tissues. Cytokine release by innate cells combined with the accumulation of Th2 cells in lung tissues are largely responsible for the massive local recruitment of eosinophils, basophils and other precursors, which ultimately promote airway hyper responsiveness and mucus secretion [2][3][4][5].DC are critical players in the initiation and maintenance of airway inflammation [6]. Three lung DC subsets have been identified in the conductive airways and the lung parenchyma with distinct functions [7]. The non-plasmacytoid signal regulatory protein a (SIRP-a) 1 DC (CD11c T-cell proliferation in vivo. Results CD47-Fc protects BALB/c mice from Th2-mediated airway inflammationWe previously demonstrated that CD47-deficient mice are protected from allergic airway inflammation [8]. Here we evaluated the impact of CD47-Fc fusion protein on the development of allergic airway inflammation in BALB/c mice. Mice administered with CD47-Fc but not control human CD47-Fc (ctrlFc) on days 0 and 5 of OVA immunization showed decreased (Fig. 1A). CD47-Fc treatment reduced the total cell counts in the BALF as well as the numbers of eosinophils, neutrophils and lymphocytes analyzed by flow cytometry (Fig. 1B and Supporting Information Fig. 1). We next examined cytokine and chemokine expression in the culture supernatants of lung explants of CD47-Fc-treated mice and found that IL-5, IL-13 and eotaxin release was significantly decreased, whereas IL-4 expression remained unchanged (Fig 1C and D). We also found a reduction in the proportio...