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CD82 and CD37 Opposing Functions of the Tetraspanins Presentation

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CD82 and CD37 Opposing Functions of the Tetraspanins Presentation The Journal of Immunology Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37 Eleanor L. Jones,* Janet L. Wee,*,† Maria C. Demaria,* Jessica Blakeley,* Po Ki Ho,* Javier Vega-Ramos,‡ Jose A. Villadangos,‡,x Annemiek B. van Spriel,{ Michael J. Hickey,† Gunther€ J. Ha¨mmerling,‖ and Mark D. Wright* 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 CD372/2 and CD822/2 BMDCs lack cellular projections, but where CD372/2 BMDCs spread poorly on fibro- nectin, CD822/2 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. The Journal of Immunology, 2016, 196: 978–987. endritic cells (DC) are the most potent of the APCs through pattern recognition receptors, they reduce MHC turnover because they have the unique ability to activate naive Ag- and upregulate expression of MHC/peptide complexes, costimu- D specific T cells (1). However, DC function varies with latory molecules such as CD80 and CD86, and proinflammatory activation state; the classical example being migratory DCs. cytokines, all of which increase their capacity to stimulate T cells by guest on September 30, 2021. Copyright 2016 Pageant Media Ltd. Unactivated migratory DCs in the periphery efficiently patrol and direct adaptive cellular immunity (2). Concurrently, DCs through tissues and are specialized for Ag uptake. These highly undergo morphological changes involving the extension of den- endocytic cells are poor stimulators of T cells, because of both drites thought to promote efficient interactions with T cells, a a moderate surface expression and a high turnover of MHC decrease in Ag uptake and processing, and a modification in cell molecules. However, once DCs receive danger signals transduced migration. Thus, rather than migrating randomly through tissue, they now migrate directionally, via the lymphatics to the draining *Department of Immunology and Pathology, Monash University, Melbourne, Victoria lymph nodes (2–4). The mechanisms of migration used by DCs 3004, Australia; †Department of Medicine, Centre for Inflammatory Diseases, Monash have been reported to be both dependent on adhesion molecules University, Clayton, Victoria 3168, Australia; ‡Department of Microbiology and Immu- x (5–7) and adhesion-independent ameboid migration, driven chiefly http://classic.jimmunol.org nology, University of Melbourne, Melbourne 3010, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University by cytoskeletal protrusion and contractile forces (8). Nonetheless, of Melbourne, Melbourne 3010, Australia; {Radboud Institute for Molecular Life the activated DC that has migrated to the draining lymph node has Sciences, Radboud University Medical Center, G525 GA Nijmegen, the Netherlands; and ‖ now metamorphosed to become a cell specialized at initiating Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany adaptive immunity by presenting Ags to naive T cells and inducing ORCIDs: 0000-0001-6015-5651 (M.C.D.); 0000-0001-6771-8891 (J.A.V.); 0000- 0002-3590-2368 (A.B.v.S.); 0000-0003-2354-357X (M.J.H.); 0000-0002-2177-5214 their activation (2). These major functional changes require ex- (M.D.W.). quisite coordination between the Ag processing and presentation Downloaded from Received for publication February 12, 2015. Accepted for publication December 1, machinery, and the myriad of adhesion, signaling, and cytoskeletal 2015. proteins that regulate DC morphology and migration. This work was supported by grants from the Australian National Health and Medical One type of protein known to regulate both Ag presentation and Research Council and the Netherlands Organization for Scientific Research (NWO- Vidi Grant 864.11.006 to A.B.v.S.). cell motility is the tetraspanins, a superfamily of four-transmembrane molecules, highly conserved in evolution and expressed in all mam- Address correspondence and reprint requests to Dr. Mark D. Wright, Monash University, Alfred Medical Research and Education Precinct, Commercial Road, malian cells. The best-defined role of tetraspanins in biology is their Melbourne, VIC 4004, Australia. E-mail address: [email protected] molecular organization of cell membranes. Tetraspanins directly The online version of this article contains supplemental material. interact with their molecular partners and organize them into signal- Abbreviations used in this article: BMDC, bone marrow–derived DC; DC, dendritic transducing microdomains (9, 10). Components of tetraspanin- cell; MHC II, MHC class II; MoDC, monocyte-derived DC; TEM, tetraspanin-enriched enriched microdomains (TEM) include membrane proteins such as microdomain; WT, wild-type. integrins, proteases that regulate cell-surface molecule expression Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 posttranslationally, and signaling molecules including kinases and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500357 The Journal of Immunology 979 phosphatases. Tetraspanins regulate the spatiotemporal molecular following primers: forward: 59-AGGTGTTTGCCCTTCTCCTT-39 and 2/2 interactions of their partner proteins and thereby influence complex reverse: 59-CCACCTGTGACAACCAAGTG-39. CD82 PCR was per- cellular events such as activation, adhesion, and migration. An formed with the following primers: forward: 59-TCCTTAAGCCTCAA- GAAAACC-39 and reverse: 59-TGTGAGGGCTCCAGTCTCC-39. PCR emerging role for TEMs is in communication between the cell program was as follows: 95˚C for 15 min, cycle: 95˚C 30 s, 50˚C 30 s, surface and the cytoskeleton. Tetraspanins regulate cytoskeletal- 72˚C 45 s, 35 cycles, 72˚C for 7 min (final annealing), and hold at 4˚C. 2 2 dependent processes such as outside-in integrin signaling and CD82 / mice were shown to lack CD82 mRNA, and levels of CD82 in WT BMDCs were measured via TaqMan real-time PCR for mouse CD82 adhesion strengthening, actin polymerization, cellular polarity, 2 2 (CD82 / expression of CD82 not shown) (Catalog Mm00492061_m1; and spreading (9–11). On the molecular level the tetraspanin Life Technologies). Levels of CD37 in WT BMDCs were measured via CD81 has been shown to interact with three important regulators TaqMan real-time PCR for mouse CD37 (Catalog Mm00514240_m1; Life of cytoskeleton polymerization: the Rho GTPase Rac, Ezrin, and Technologies). Levels of 18S were measured by TaqMan real-time PCR Moesin. Ezrin and Moesin are peripheral membrane proteins that for mouse 18S (Catalog Mm_03928990_g1; Life Technologies). Real-time link the cytoskeleton with the plasma membrane (11). PCR was performed according to the manufacturer’s guidelines. In APCs, tetraspanins have been implicated in many facets of Cell isolation biology including pattern recognition (12), Ag presentation (13), DCs were isolated as previously described (14). In brief, bone marrow was and cell migration (14). A role for tetraspanins in Ag processing is cultured for 7–9 d with 10 ng/ml GM-CSF and IL-4 (R&D Systems) to suggested both by their presence in MHC class II compartments, obtain BMDCs, and activated with 1 mg/ml LPS. Spleens were treated with where they associate with MHC class II and the peptide editors enzymatic digestion and density-gradient centrifugation before magnetic HLA-DM and HLA-DO (15–17), and by their association with bead depletion to obtain splenic DCs. T cells were isolated as previously described (31). In brief, spleens and lymph nodes were prepared into a MHC I and II at the cell surface (15, 18). However, the conse- single-cell suspension before being subjected to magnetic bead depletion. quences of these interactions on Ag presentation are incompletely understood, with studies variously pointing to roles in promoting Expression of CD82 and CD37 on human DCs (19) and restraining Ag presentation (20, 21). Human PBMCs were isolated from buffy coats and monocytes were Recently, we have demonstrated that the tetraspanin CD37 plays enriched by plastic adherence. Monocytes were cultured with 450 U/ml an important role in linking Ag processing and presentation with GM-CSF (Strathmann) and 300 U/ml IL-4 (Strathmann) in complete cell migration during DC activation. CD37
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