Dendritic cells (DCs) capture and process Ag in the periphery. Thus, traffic through lymphatic vessels is mandatory before DCs relocate to lymph nodes where they are dedicated to T-cell priming. Here, we show that the ubiquitous self-marker CD47 selectively regulates DC, but not T and B cell trafficking across lymphatic vessels and endothelial barriers in vivo. We find an altered skin DC migration and impaired T-cell priming in CD47-deficient mice at steady state and under inflammatory conditions. Competitive DC migration assays and active immunization with myeloid DCs demonstrate that CD47 expression is required on DCs but not on the endothelium for efficient DC trafficking and T-cell responses. This migratory defect correlates with the quasi-disappearance of splenic marginal zone DCs in nonmanipulated CD47-deficient mice. Nonetheless, CCR7 expression and CCL19-driven chemotaxis remain intact. Our data reveal that CD47 on DCs is a critical factor in controlling migration and efficient initiation of the immune response.

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.

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. In the present study, we report that basophils can be detected in the mucosa of Th17-associated lung and inflammatory bowel disease and accumulate in inflamed colons containing large quantities of IL-33. We also demonstrate that circulating basophils increased memory Th17 responses. Accordingly, IL-3-or IL-33-activated basophils amplified IL-17 release in effector memory T cells (T EM ), central memory T cells (T CM) IntroductionBasophils are the least abundant of the granulocyte population, accounting for only 0.5%-1% of circulating leukocytes, and, together with eosinophils and mast cells (MCs), have long been associated with allergic diseases and helminth infections. [1][2][3][4] Like MCs, basophils express the tetrameric form of the high-affinity receptor for IgE (Fc⑀RI) and are a major source of histamine, which is stored in their cytoplasmic basophilic granules. Basophils and MCs belong to distinct cell lineages and are biologically very different. 5 Basophils are short-lived circulating cells (estimated half-life of 2 days) that differentiate and mature in the BM, whereas MCs are long-lived, tissue-resident cells that differentiate in peripheral tissues from locally recruited circulating CD34 ϩ precursors released from the BM. MCs are easily detectable at the interface of the organism with the external world; in contrast, basophils are rarely found in normal tissues, but can be detected by immunohistochemistry in inflamed tissues of patients with asthma, allergic rhinitis, and various allergic skin diseases. 1,6,7 However, the presence of basophils in the mucosa of patients with inflammatory diseases that are independent of IgE has not been reported.The CD4 T cells play a key role in orchestrating the pathologic immune reaction of chronic inflammatory disorders. It is now known that Th17 effectors play a crucial role in pulmonary cystic fibrosis (CF). 8 Similarly, Th17 and Th1 cells are involved in mucosa-associated chronic disorders such as inflammatory bowel disease (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC). 9-11 Specifically, CD is a chronic and relapsing T cell-driven inflammatory disease of the entire gastrointestinal tract. CD4 effector T cells are generated in draining lymph nodes and recruited into the intestinal tissues, where they contribute to the inflammatory process and tissue destruction. 9 Once initiated, inflammation is first characterized by the expression of proinflammatory cytokines involved in innate immunity (ie, IL-12, TNF-␣, and IL-23), followed by those involved in adaptive immunity (ie, . 9,12 APC-derived IL-1␤, together with IL-6, promotes the development of human Th17 cells in vitro. 13 IL-23 promotes the expansion of memory Th17 cells. 14 In mice, IL-23 drives pathogenic Th17/Th1 cells. 15 Double IL-17-and IFN-␥-producing CD4 T cells ar...

The cytokine milieu and dendritic cells (DCs) direct Th1 development. Yet, the control of Th1 polarization by T cell surface molecules remains ill-defined. We here report that CD47 expression on T cells serves as a self-control mechanism to negatively regulate type 1 cellular and humoral immune responses in vivo. Th2-prone BALB/c mice that lack CD47 (CD47−/−) displayed a Th1-biased Ab profile at steady state and after immunization with soluble Ag. CD47−/− mice mounted a T cell-mediated exacerbated and sustained contact hypersensitivity (CHS) response. After their adoptive transfer to naive CD47-deficient hosts 1 day before immunization with soluble Ag, CD47−/− as compared with CD47+/+CD4+ transgenic (Tg) T cells promoted the deviation of Ag-specific T cell responses toward Th1 that were characterized by a high IFN-γ:IL-4 cytokine ratio. Although selective CD47 deficiency on DCs led to increased IL-12p70 production, CD47−/−Tg T cells produced more IFN-γ and displayed higher T-bet expression than CD47+/+ Tg T cells in response to OVA-loaded CD47−/− DCs. CD47 as part of the host environment has no major contribution to the Th1 polarization responses. We thus identify the CD47 molecule as a T cell-negative regulator of type 1 responses that may limit unwanted collateral damage to maximize protection and minimize host injury.