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

Abstract

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.

C-type lectin-like receptor 2 (CLEC-2)-dependent DC migration is controlled by tetraspanin CD37

“…This is in accordance with studies showing impaired migration of Cd37-/-DCs in vivo (Gartlan et al, 2013;Jones et al, 2016). In DC biology, tetraspanin interactions with adhesion receptors or MHC molecules are particularly important for antigen presentation and T cell activation (Sheng et al, 2009;Gartlan et al, 2010;Jones et al, 2016;Rocha-Perugini et al, 2017). Now, we demonstrate a specific role for CD37 in controlling CLEC-2 function in migration of DCs.…”

“…downregulation of RhoA and upregulation of Rac1) (Acton et al, 2012), we postulate that the underlying molecular mechanism of the defective cell migration of Cd37-/-DCs is due to deregulation of intracellular Rho GTPases as a consequence of impaired recruitment of CLEC-2 to its ligand podoplanin. This is supported by a recent study demonstrating impaired activation of Rac-1 in toxin-activated adherent Cd37-/bone marrow-derived DCs (Jones et al, 2016). Altogether, these data support a model in which CD37 is important for CLEC-2 recruitment in the plasma membrane of myeloid cells upon podoplanin binding, which results in Syk activation and changes in Rho GTPase activity (e.g.…”

“…The importance of CD37 in the immune system has been demonstrated in CD37-deficient mice (Cd37-/-) that have defective humoral and cellular immune responses (van Spriel et al, , 2012. Interestingly, DCs that lack CD37 showed impaired spreading, adhesion and migration, leading to defective initiation of the cellular immune response (Gartlan et al, 2013;Jones et al, 2016). Since CLEC-2 plays an important role in DC migration (Acton et al, 2012), and its homologous receptor Dectin-1 has been shown to interact with tetraspanin CD37 (Meyer-Wentrup et al, 2007), we hypothesized that CD37 may influence CLEC-2 membrane organization and thereby controls DC migration.…”

Fibroblastic Reticular Cell Response to Dendritic Cells Requires Coordinated Activity of Podoplanin, CD44 and CD9

“…Podoplanin drives actomyosin contrac-tility in FRCs (24,25). Tetraspanin CD82 also controls cytoskeletal structures via RhoGTPase signalling (42)(43)(44)(45), and loss of CD82 in osteoclasts decreases the level of podoplanin expression (42). We hypothesized that tetraspanin CD82 may regulate podoplanin-driven actomyosin contractility in FRCs.…”

Migration of intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation

“…1B). As DC migration and activation, both crucial events for the induction of immunity, can be regulated independently (Jones et al, 2016;Yrlid et al, 2006), we also measured the expression of the costimulatory molecule CD86 as a surrogate marker for DC activation. Again, activation of both DC subsets was also entirely depended on TLR3 and TRIF expression ( Fig.…”