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Dissociation the Immunological Synapse Upon Cellular T Cells

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Dissociation the Immunological Synapse Upon Cellular T Cells Peptide-Specific Intercellular Transfer of MHC Class II to CD4 + T Cells Directly from the Immunological Synapse upon Cellular Dissociation This information is current as of September 26, 2021. Scott A. Wetzel, Timothy W. McKeithan and David C. Parker J Immunol 2005; 174:80-89; ; doi: 10.4049/jimmunol.174.1.80 http://www.jimmunol.org/content/174/1/80 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2004/12/16/174.1.80.DC1 Material http://www.jimmunol.org/ References This article cites 53 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/174/1/80.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Peptide-Specific Intercellular Transfer of MHC Class II to CD4؉ T Cells Directly from the Immunological Synapse upon Cellular Dissociation1 Scott A. Wetzel,2* Timothy W. McKeithan,† and David C. Parker3* The transfer of membrane proteins from APC to T cells was initially described in the 1970s, and subsequent work has described two mechanisms of transfer: APC-derived exosomes and direct transfer of small packets, while cells remain conjugated. Using fibroblast APC expressing a GFP-tagged I-Ek molecule with covalently attached antigenic peptide, we observed a third mechanism in live cell imaging: T cells spontaneously dissociating from APC often capture MHC:peptide complexes directly from the im- munological synapse. Using two I-Ek-restricted murine TCR transgenic T cells with different peptide specificity, we show in this study that the MHC transfer is peptide specific. Using blocking Abs, we found that MHC:peptide transfer in this system requires Downloaded from direct TCR-MHC:peptide interactions and is augmented by costimulation through CD28-CD80 interactions. Capture of the GFP-tagged MHC:peptide complexes correlates with an activated phenotype of the T cell, elevated CD69 with down-modulated TCR. The transferred MHC:peptide molecules transferred to the T cell are associated with molecules that imply continued TCR signaling; p56lck, phosphotyrosine, and polarization of the actin cytoskeleton. The Journal of Immunology, 2005, 174: 80–89. lymphocyte recognition of cognate MHC:peptide com- some/vesicle mediated (17–19) or requiring direct cell-cell contact. http://www.jimmunol.org/ plexes results in the accumulation of cytoplasmic and Recently, several groups have shown that for TCR-mediated cap- T membrane-bound proteins to the contact region (1, 2). ture, the immunological synapse is the location of transfer, while These molecules are spatially and temporally segregated into dis- the cells remain conjugated (20–23). This transfer is Ag dependent tinct supramolecular activation complexes (SMACs)4 (3). The cen- (20, 22), but it is unknown whether transfer involves only specific tral supramolecular activation complex (c-SMAC) contains en- MHC:peptide molecules or whether nonspecific MHC:peptide li- gaged TCR/MHC:peptide, CD28/CD80, and signaling-associated gands are also transferred. The specificity of transfer may be crit- ␪ molecules such as protein kinase C (PKC)- and tyrosine-phos- ical in controlling immune responses in vivo, as T cells functioning phorylated proteins surrounded by a peripheral SMAC containing, as APCs in vivo can induce anergy (24, 25). The stripping of among others, adhesion molecules such as ICAM-1/LFA-1 (3, 4). specific MHC:peptide complexes from an APC may also provide by guest on September 26, 2021 The role of this immunological synapse is still unclear. It is widely a mechanism for T cell competition for MHC:peptide ligands, thus accepted that it functions in sustaining TCR-mediated intracellular increasing the affinity of a specific response (26). The potential signaling (4–7), but data from others have suggested that its main role of the T cell immunological synapse in MHC transfer is function is the polarized secretion of effector molecules (8–12). strengthened by the fact that both B cells (27, 28) and NK cells Alternatively, Shaw and colleagues (13) have hypothesized that (29–32) form immunological synapses and capture membrane pro- the synapse regulates TCR down-modulation and endocytosis. teins directly from them. Another potential role of the immunological synapse is the cap- ture of membrane-bound molecules from APCs. The literature on The mechanism of direct cell-to-cell, contact-dependent transfer acquisition of MHC molecules by T cells from APC dates back in T-APC conjugates is unknown. It has been characterized by the over 20 years (14–16). Capture has been characterized as exo- transfer of multiple small packets of APC membrane containing surface proteins such as MHC (20), CD80 (33), and OX40L (34), while the cells remain conjugated. It is possible that this form of *Department of Molecular Microbiology and Immunology, Oregon Health & Science transfer is the result of exosomal release from the APC and sub- University, Portland, OR 97239; and †Department of Pathology and Microbiology, sequent uptake in the region of the immunological synapse. This is University of Nebraska Medical Center, Omaha, NE 68198 supported by a recent report from Boes et al. (35) showing polar- Received for publication April 26, 2004. Accepted for publication October 22, 2004. ized MHC class II delivery to the T cell-dendritic cell interface. The costs of publication of this article were defrayed in part by the payment of page Additionally, electron microscopy data from Patel et al. (19) dem- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. onstrate the presence of APC-derived exosomes in the space be- 1 This work was supported by Grant AI29544 from the National Institutes of Health tween T cells and APCs at the T-APC interface. However, this is and a grant from the Oregon Health Sciences Foundation. not the only method of transsynaptic capture. Stinchcombe et al. 2 Current address: Division of Biological Sciences and Center for Environmental (11) showed by electron microscopy that during the process of Health Sciences, University of Montana, Missoula, MT 59812. spontaneous CTL release from target cells, small membrane 3 Address correspondence and reprint requests to Dr. David C. Parker, Department of bridges formed and that MHC class I molecules and yellow fluo- Molecular Microbiology and Immunology, L220, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail address: rescent protein-tagged APC membrane were subsequently trans- [email protected] ferred to the T cell upon dissociation. Such dissociation-associated 4 Abbreviations used in this paper: SMAC, supramolecular activation complex; c- transfer is consistent with the finding that during transendothelial SMAC, central SMAC; DIC, differential interference contrast microscopy; FKBP, FK506-binding protein; Hb, murine hemoglobin peptide; MCC, moth cytochrome c migration, T cells acquire endothelial membrane and membrane peptide; MFI, mean fluorescence intensity; PKC, protein kinase C. proteins such as CD31, CD49d, CD54, CD61, and CD62E (36). Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 81 Using fibroblasts expressing a GFP-tagged covalent MHC:pep- resuspended in RPMI 1640 (Invitrogen Life Technologies) containing sup- tide construct and costimulatory molecules (37) as APC, in this plements, as described for complete DMEM (complete RPMI 1640). Cells ␮ study we have characterized the transfer of MHC:peptide com- were primed in vitro with 2.5 M peptide (MCC 88–103 for AD10; Hb 64–76 for 3.L2) for 4–6 days with addition of 10 U/ml exogenous IL-2 on plexes from APC to T cells directly from the immunological syn- day 2. Lymphocytes were isolated from primed cultures by density centrifu- apse as a result of spontaneous cellular dissociation. In this system, gation using Lympholyte M (Cedarlane Laboratories). T cells were resus- MHC transfer is mediated by TCR/MHC interactions and is aug- pended at 5 ϫ 106/ml in complete phenol red-free RPMI 1640 for use. mented by CD28/CD80 costimulation. Using T cells from TCR Live cell microscopy transgenic mice specific for a different antigenic peptide presented 5 by I-Ek, we show in this work for the first time that the transsyn- For live cell microscopy, 2.5 ϫ 10 APCs were seeded into 0.17-mm Delta T culture dishes (Bioptechs) 1 day before the experiment in 1 ml of com- aptic transfer of MHC following Ag recognition is specific for plete DMEM. Dishes were fitted into a Bioptechs TC3 heated stage adapter MHC molecules loaded with cognate peptide. The extent of MHC: and maintained at 37°C for the duration of the imaging. After adding 2.5 ϫ peptide transfer to the T cells is associated with an activated phe- 105 AD10 T cells to the dish, alternating ϫ400 or ϫ600 green fluorescent notype (CD69high, TCR down-modulated). Finally, we report that (528 nm) and differential interference contrast (DIC) images were taken the transferred MHC:peptide molecules are found on the surface of every 8–12 s for 45 min with the Applied Precision Instruments Delta- Vision image restoration system.
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