Tetraspanin CD 37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

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Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin–dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1–adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

Section: Flow Chamber Assaymentioning

confidence: 99%

“…CD37 has also been shown to control functions in T cells and dendritic cells (19)(20)(21)(22). Notably, we recently demonstrated that CD37 promotes migration of dendritic cells (23). CD37 is also expressed in granulocytes (24), but its role in these cells has not been examined.…”

mentioning

confidence: 99%

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Wee

Schulze

Jones

et al. 2015

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“…In APCs, tetraspanins have been implicated in many facets of biology including pattern recognition (12), Ag presentation (13), and cell migration (14). A role for tetraspanins in Ag processing is suggested both by their presence in MHC class II compartments, where they associate with MHC class II and the peptide editors HLA-DM and HLA-DO (15)(16)(17), and by their association with MHC I and II at the cell surface (15,18).…”

mentioning

confidence: 99%

Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37

Jones

Wee

Demaria

et al. 2016

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This study supports a new concept where the opposing functions of the tetraspanins CD37 and CD82 may coordinate changes in migration and Ag presentation during dendritic cell (DC) activation. We have previously published that CD37 is downregulated upon monocyte-derived DC activation, promotes migration of both skin and bone marrow–derived dendritic cells (BMDCs), and restrains Ag presentation in splenic and BMDCs. In this article, we show that CD82, the closest phylogenetic relative to CD37, appears to have opposing functions. CD82 is upregulated upon activation of BMDCs and monocyte-derived DCs, restrains migration of skin and BMDCs, supports MHC class II maturation, and promotes stable interactions between T cells and splenic DCs or BMDCs. The underlying mechanism involves the rearrangement of the cytoskeleton via a differential activation of small GTPases. Both CD37−/− and CD82−/− BMDCs lack cellular projections, but where CD37−/− BMDCs spread poorly on fibronectin, CD82−/− BMDCs are large and spread to a greater extent than wild-type BMDCs. At the molecular level, CD82 is a negative regulator of RhoA, whereas CD37 promotes activation of Rac-1; both tetraspanins negatively regulate Cdc42. Thus, this study identifies a key aspect of DC biology: an unactivated BMDC is CD37hiCD82lo, resulting in a highly motile cell with a limited ability to activate naive T cells. By contrast, a late activated BMDC is CD37loCD82hi, and thus has modified its migratory, cytoskeletal, and Ag presentation machinery to become a cell superbly adapted to activating naive T cells.

“…In vivo DC migration was studied by FITC-painting experiments, as described previously (29). Briefly, abdominal skin was shaved prior to applying a FITC solution.…”

Section: Fitc Paintingmentioning

confidence: 99%

“…Ear emigration assays were performed as described previously (29). Briefly, dorsal and ventral skin sheets were placed in medium containing 1 mg/ml LPS alone or LPS and 1 mg/ml CCL21 and cultured for 48 h. Emigrated DCs were quantified using flow cytometry.…”

Section: Ear Emigrationmentioning

confidence: 99%

Semaphorin 7A Promotes Chemokine-Driven Dendritic Cell Migration

Rijn

Paulis

Riet

et al. 2016

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Dendritic cell (DC) migration is essential for efficient host defense against pathogens and cancer, as well as for the efficacy of DC-based immunotherapies. However, the molecules that induce the migratory phenotype of DCs are poorly defined. Based on a large-scale proteome analysis of maturing DCs, we identified the GPI-anchored protein semaphorin 7A (Sema7A) as being highly expressed on activated primary myeloid and plasmacytoid DCs in human and mouse. We demonstrate that Sema7A deficiency results in impaired chemokine CCL21-driven DC migration in vivo. Impaired formation of actin-based protrusions, resulting in slower three-dimensional migration, was identified as the mechanism underlying the DC migration defect. Furthermore, we show, by atomic force microscopy, that Sema7A decreases adhesion strength to extracellular matrix while increasing the connectivity of adhesion receptors to the actin cytoskeleton. This study demonstrates that Sema7A controls the assembly of actin-based protrusions that drive DC migration in response to CCL21.