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Memory/Effector T Cells Invadosome-Like Protrusions Formed by Antigen Recognition Is Facilitated By Antigen Recognition Is Facilitated by Invadosome-like Protrusions Formed by Memory/Effector T Cells This information is current as Peter T. Sage, Laya M. Varghese, Roberta Martinelli, Tracey of September 26, 2021. E. Sciuto, Masataka Kamei, Ann M. Dvorak, Timothy A. Springer, Arlene H. Sharpe and Christopher V. Carman J Immunol 2012; 188:3686-3699; Prepublished online 21 March 2012; doi: 10.4049/jimmunol.1102594 Downloaded from http://www.jimmunol.org/content/188/8/3686 Supplementary http://www.jimmunol.org/content/suppl/2012/03/21/jimmunol.110259 Material 4.DC1 http://www.jimmunol.org/ References This article cites 79 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/188/8/3686.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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antigen Recognition Is Facilitated by Invadosome-like Protrusions Formed by Memory/Effector T Cells Peter T. Sage,*,† Laya M. Varghese,† Roberta Martinelli,† Tracey E. Sciuto,‡ Masataka Kamei,† Ann M. Dvorak,‡ Timothy A. Springer,x Arlene H. Sharpe,* and Christopher V. Carman† Adaptive immunity requires that T cells efficiently scan diverse cell surfaces to identify cognate Ag. However, the basic cellular mechanisms remain unclear. In this study, we investigated this process using vascular endothelial cells, APCs that possess a unique and extremely advantageous, planar morphology. High-resolution imaging revealed that CD4 memory/effector T cells dynamically probe the endothelium by extending submicron-scale, actin-rich “invadosome/podosome-like protrusions” (ILPs). The intimate intercellular contacts enforced by ILPs consistently preceded and supported T cell activation in response to endothelial MHC class II/Ag. The resulting calcium flux stabilized dense arrays of ILPs (each enriched in TCR, protein kinase C-u, ZAP70, phosphotyr- Downloaded from osine, and HS1), forming what we term a podo-synapse. Similar findings were made using CD8 CTLs on endothelium. Further- more, careful re-examination of both traditional APC models and professional APCs suggests broad relevance for ILPs in facilitating Ag recognition. Together, our results indicate that ILPs function as sensory organelles that serve as actuators of immune surveillance. The Journal of Immunology, 2012, 188: 3686–3699. http://www.jimmunol.org/ daptive immunity relies on the ability of TCRs ex- MHC/Ag. However, the surfaces of all cells are modified by a pressed on lymphocytes to efficiently recognize peptide relatively thick (50–500 nm) gel-like polysaccharide coat termed A Ag bound to MHC molecules (1). During the priming the glycocalyx (3), which provides a formidable energy barrier phase, naive lymphocytes must constitutively scan professional (via steric and electrostatic repulsion) to close membrane–mem- APCs within lymph nodes. During the effector phase, memory/ brane encounter (4, 5). In this way, TCR and MHC are effectively effector T cells need to effectively survey an extremely wide range shielded and immune recognition is opposed (5–10). Thus, a of APCs and potential target cells within peripheral tissues. fundamental question is, how do T cells overcome this energy Fundamental cellular mechanisms for such immune surveillance barrier to engage immune receptors? activities remain incompletely understood. It has long been appreciated that as a consequence of Ag rec- by guest on September 26, 2021 At the heart of immune surveillance is the requirement for ognition, specialized cell–cell interfaces form that involve mem- T cells to form extremely intimate (∼14 nm, the total height of the brane alignment, cytoskeletal remodeling, clustering/segregation TCR–MHC complex) (2) contacts with apposing cells to sample of immune receptors/adhesion molecules, and glycocalyx com- ponents (5, 11–15). These “immunological synapses” (ISs) form within minutes of Ag recognition and are thought to amplify and *Department of Microbiology and Immunobiology, Harvard Medical School, Boston, sustain signaling, as well as facilitate exchange of cytokine and/or MA 02115 †Department of Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; cytotoxic materials (5, 11–15). However, detailed mechanisms ‡Department of Pathology, Center for Vascular Biology Research, Beth Israel Dea- x facilitating initial Ag sampling between T cells and APCs, and coness Medical Center, Harvard Medical School, Boston, MA 02215; and Department how these lead to early IS formation, are not completely under- of Pathology, Immune Disease Institute, Harvard Medical School, Boston, MA 02115 stood (16, 17). This stems from technical challenges associated Received for publication September 14, 2011. Accepted for publication February 13, 2012. with irregular topologies of APC surfaces and poorly controlled This work was supported by the National Institutes of Health (Grants T32 AI070085 orientation of the cell–cell interaction planes, issues that pro- to P.T.S., AI078897 to A.H.S., and HL04006 to C.V.C.) and the American Heart foundly limit the requisite imaging approaches (16–18). Association, the Arthritis Foundation, and the Roche Organ Transplant Research Investigators have partially circumvented these restrictions by Foundation (to C.V.C.). developing planar substrate models (i.e., lipid bilayers and Ab- Address correspondence and reprint requests to Christopher V. Carman, Harvard Medical School—Beth Israel Deaconess Medical Center, 330 Brookline Avenue, coated surfaces) that provide optimal spatiotemporal resolution RN234, Boston, MA 02215. E-mail address: [email protected] for monitoring Ag response dynamics (19–23). These models have The online version of this article contains supplemental material. afforded invaluable insights, such as the discovery of TCR micro- Abbreviations used in this article: BMDC, bone marrow-derived dendritic cell; clusters as critical mediators of effective signaling (15, 19–22). CAMKII, calcium-calmodulin–dependent kinase II; CHO, Chinese hamster ovary; However, these systems lack key features of cellular APC surfaces, DC, dendritic cell; EC, endothelial cell; HDMVEC, human dermal microvascular such as the glycocalyx, topological deformability, and molecular EC; HLMVEC, human lung microvascular EC; HS1, hematopoietic lineage cell- specific protein 1; HUVEC, human umbilical vein EC; ILP, invadosome/podosome- complexity. Therefore, it remains uncertain how to translate such like protrusion; IRM, interference reflection microscopy; IS, immunological synapse; findings to physiologic cell–cell immune surveillance. iTmem, induced/expanded human T memory cell; mem-DsRed, palmitoylated DsRed; mem-YFP, palmitoylated YFP; MHC-I, MHC class I; MHC-II, MHC In this study, we used vascular endothelial cells (ECs) as a class II; nTmem, natural human T memory cell; PKC, protein kinase C; SA, planar APC model to interrogate the details of initial Ag recogni- streptavidin; SEB, staphylococcal enterotoxin B; TSST, toxic shock syndrome tion dynamics on a physiologic cellular substrate. ECs represent the toxin 1. interface between the blood circulation and tissue, and play critical Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 roles in regulating immune cell trafficking (1, 24, 25). The dis- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102594 The Journal of Immunology 3687 covery that ECs express MHC class I (MHC-I), MHC class II T cells were added to 8-mm pore transwell inserts that were preceded with (MHC-II), and a large number of costimulatory molecules (e.g., ECs and then collected from the bottom chamber 6 h later and analyzed by CD40, LFA-3, ICOSL, 4-1BB, OX40L, TL1A, PD-L1, but not flow cytometry. CD80 and CD86) has led to the controversial hypothesis that Live-cell imaging and analysis endothelium can also function as a type of APC (26–28). Indeed, Live-cell imaging was performed on an Axiovert S200 microscope with several studies have demonstrated that endothelium can effec- Axiovision software (Zeiss). For calcium imaging, T cells were pre- tively restimulate CD4 and CD8 memory/effector, but not naive, incubated with 1 mg/ml Fura-2–AM or Fluo-4–AM (Invitrogen) for 30 T cells (29–33). Critically, when grown in vitro, ECs form virtu- min. For Fura-2, standard Fura-2 filters were used according to manu- ally planar cell surfaces that are ideal for high spatiotemporal facturer’s instructions (Chroma) and ratiometric calcium flux was calcu- lated (340nmEX-510nmEM-background/380nmEX-510nmEM-background) resolution imaging of topological dynamics (34). for each cell using Axiovision. For Fluo-4, green fluorescence filters This study provides a detailed investigation
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