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192 Opinion TRENDS in Immunology Vol.22 No.4 April 2001 Environmental control of immunological synapse formation and duration Michael L. Dustin, Paul M. Allen and Andrey S. Shaw The coordination of T-cell migration and antigen recognition is crucial for an effective immune response. We have proposed that this coordination is achieved by formation of an immunological synapse between the T cell and the antigenpresenting cell (APC). Our view contrasts with the serial encounter model also proposed in this issue of Trends in Immunology, which is based on transient T cell–APC interactions when surrounded by collagen. Here, we propose a model that reconciles immunological synapse formation and serial encounters based on environmental control of immunological synapse formation. Michael L. Dustin* Paul M. Allen Andrey S. Shaw Center for Immunology and the Dept of Pathology, Washington University School of Medicine, 660 S. Euclid Ave, St Louis, MO 63110, USA. *Present address: Program in Molecular Pathogenesis and the Dept of Pathology, Skirball Institute of Molecular Medicine, and New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA. e-mail: dustin@ saturn.med.nyu.edu Understanding the requirements for T-cell activation is fundamental to the design of immune-based therapies for vaccination or to treat disease. The T cell and antigen-presenting cell (APC) interact via the formation of an organized immunological synapse (IS) that produces a stop signal for T-cell migration that lasts for hours or even days1–5. However, it is also becoming clear that T cell–APC interactions could be profoundly regulated by their tissue microenvironment and these effects might adjust the threshold for synapse formation and set the duration of interaction6,7. The duration of T-cell receptor (TCR) engagement has profound effects on T-cell activation and differentiation8. In this issue of Trends in Immunology, Friedl and Gunzer9 propose a model for T-cell activation based on serial encounters between T cells and APCs within collagen gels that challenges the role of IS formation. We suggest that Friedl and Gunzer take too broad an interpretation of their data, and that IS formation is still a crucial event in the immune response. Friedl and Gunzer9 have identified another aspect of T-cell behavior that is readily incorporated into our model and is helpful in explaining the structural organization of lymphoid tissues. We propose that environmental factors, such as collagen extracellular matrix and certain chemokine gradients, regulate IS formation to restrict the site of primary immune responses and to control the duration of T-cell encounters with the APC. We have proposed that T-cell activation requires formation of an IS, a supramolecular structure at the interface between the T cell and a single APC that is stable for many hours4. The IS provides a molecular machinery for integration of MHC–peptide quality and quantity. The first step in IS formation is a stop signal delivered by agonist MHC–peptide complexes. The stop signal is defined as a >10-time reduction in T-cell migration velocity as a result of contact with antigen that is sustained over a period of an hour. We have found that this step in IS formation is subject to regulation by environmental signals including dominant chemokines (e.g. SLC, ELC and IP-10)6. Dominant chemokine gradients allow T cells to migrate through the antigen stop signal, but do not induce a state of non-responsiveness because the T cells can go on to form IS and proliferate when removed from the chemokine gradient. Dominant chemokines allow for environmental control of immunological synapse formation. More recently, Friedl and colleagues found that T cells that interact with dendritic cells in collagen gels in vitro do not stop in response to agonist MHC–peptide complexes. Instead, rapidly migrating T cells transiently synapse with many antigenpositive dendritic cells7. This is similar to classical models for cytotoxic T-cell killing of multiple targets10. Although the molecular basis of this effect of collagen is not known, the implication is that signals from collagen or associated proteins and dendritic cells synergize to prevent the antigen stop signal, while retaining the ability to fully activate T cells. Collagen is essential for this effect because T cells and dendritic cells form agonist MHC–peptidedependent clusters in suspension cultures (cell–cell ‘...environmental factors regulate IS formation to restrict the site of primary immune responses and to control the duration of T-cell encounters with the APC.’ contacts with minimal cell–matrix contacts). These clusters are consistent with the function of a stop signal, although the internal dynamics of the clusters were not directly evaluated. Friedl and Gunzer9 propose a serial encounter model to explain T-cell activation without IS formation and to explain how this mode of interaction might produce outcomes of proliferation and anergy depending upon the frequency of interactions. Our view is that collagen provides a new axis for regulation of IS formation and this might help to explain the unique organization of collagen in secondary lymphoid tissues. Regarding the molecular basis of signal integration by migrating lymphocytes versus stopped lymphocytes, the major difference is polarization and not adhesive strength. Migrating cells engage the same number of adhesion molecules as stationary cells, but the pattern of engagement is different. In a migrating cell, the adhesion molecules are asymmetric, with molecules accumulating at the rear as they are moved backwards by cytoskeletal tension http://immunology.trends.com 1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)01872-5 Opinion Fig. 1. Testing TCR interaction by migration versus immunological synapse formation. (a) shows a migrating cell – the increasing red color represents the accumulation of adhesion molecules. The arrow represents cytoskeletal tension. Green represents the accumulation of MHC–peptide before they disengage from TCR. (b) shows the immunological synapse formation. Symbols are the same as in (a), but the adhesion molecules accumulate towards the center of the synapse as a result of the central orientation of cytoskeletal tension. MHC–peptide accumulated by the parallel engaged TCR in the back. TRENDS in Immunology Vol.22 No.4 April 2001 (a) (b) Migration: MHC–peptide disengage Immunological synapse: MHC–peptide accumulate TRENDS in Immunology (Fig. 1). By contrast, stopped cells sweep molecules toward the center of the synapse and thus accumulate molecules in a radial bulls eye pattern. The migrating T cell will detach from the APC within minutes and does not form a stable complex of TCR and MHC–peptide, whereas the stopped cells accumulates MHC–peptide complexes in the center of the IS to generate a zone of parallel TCR engagement. Therefore, any unique signals produced by the parallel engagement of TCR in the center of the IS (cSMAC) must be replaced by other signals provided by the collagen gel or dendritic cells under conditions of the Friedl study. There are several mechanisms by (a) (b) Naive T cell no collagen – immunological synapse (c) Naive T cell in collagen gel – transient interaction (d) Naive T cell collagen sequestered – immunological synapse Effector T cell in collagen gel – α1β1 α2β1 anchors slow exit TRENDS in Immunology Fig. 2. Collagen regulates immunological synapse formation. (a) In the absence of collagen fibrils and dominant chemokine gradients the T cell stops migrating on contact with antigen bearing antigenpresenting cell (APC) leading to an immunological synapse. (b) In the presence of collagen fibrils the T cell does not stop on contact with antigen bearing APC leading to serial encounters. (c) The hypothesis is that in the lymph node the collagen fibrils are enclosed in fibroblastic reticular cell sheath so the T cell forms an immunological synapse with antigen bearing APC. (d) Expression of high affinity collagen receptors VLA-1 and VLA-2 could help retain antigen specific effector cells in collagen rich inflammatory sites. http://immunology.trends.com 193 which extracellular matrix signaling could provide a co-stimulatory signal that contributes to full T-cell activation11,12. It is also possible that dendritic cells might present MHC–peptide complexes and co-stimulatory molecules in a pre-associated form that could accelerate signaling compared with other APC types13. It is notable that MHC–peptide complexes that interact with TCR in a sub-optimal manner actually signal, but fail to stop the T cell and fail to form an immunological synapse. Instead, the T cells exposed to these partial agonist ligands migrate while signaling in a manner that leads to weak or absent proliferation4. Thus, tolerance might result when T cells signal on the move, but in the absence of collagen. In the presence of collagen, a stray naive T cell might simply remain ignorant of its antigen encounters and exit harmlessly through lymphatics before achieving a superthreshold stimulus. The finding that collagen is a potent negative regulator of IS formation provides a rationale for the mysterious organization of collagen fibers in the lymph nodes, the most well-characterized site for efficient primary immune responses14. The T-cell area of resting lymph nodes is a cellular environment with little or no collagen in contact with T cells. The abundant collagen fibers are sheathed in stromal cells to form the reticular fiber network. Lymphocytes pass through this collagen-rich space during extravasation, but then enter the collagenfree parenchyma, which is most similar to a dense suspension of T cells laced with reticular cells and dendritic cells (Fig. 2). Upon entry into lymph nodes, the key dominant chemokine receptor SLC is probably desensitized (during initial arrest on the high endothelial venule surface15) and the T cells will thus be in an optimal environment for IS formation. The suspension-like nature of the T-cell areas of lymph nodes is consistent with the demonstration of clear antigen-dependent T cell–dendritic cell clusters in lymph nodes in vivo16, similar to those observed by Friedl in suspension cultures without collagen7. These data are not consistent with a general serial encounter model and are more consistent with the formation of IS in lymph nodes in the 24–48 h time frame following injection of antigen-positive dendritic cells in vivo. Direct observations of T cell–APC dynamics in lymph nodes in vivo will be required to pass the ‘in vivo veritas’ test of IS formation versus the serial encounter model. This test might not be too far in the future as technologies of vital microscopy and deep penetrating two-photon excitation microscopy17 are poised to reveal the true nature of the potent kiss between the T cell and the dendritic cell. By contrast, T cells in the dermis and other solid tissues would always be exposed to abundant collagen and thus would interact in a serial encounter mode that might be ideal for T-cell effector functions, as highlighted by Friedl7. Thus, the environment of the T cell could define the duration of interactions. In 194 Opinion TRENDS in Immunology Vol.22 No.4 April 2001 this model IS formation is favored in secondary lymphoid tissues, the primary site of naive T-cell activation. Interestingly, the B-cell follicles, in which T–B cell collaboration is focused, are even free of reticular fibers and would also be ideal locations to form the well-characterized T cell–B cell IS (Refs 1,18). However, effector cells in the periphery will interact with many macrophages to promote References 1 Monks, C.R. et al. (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 2 Dustin, M.L. et al. (1997) Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc. Natl. Acad. Sci. U. S. A. 94, 3909–3913 3 Dustin, M.L. et al. (1998) A novel adapter protein orchestrates receptor patterning and cytoskeletal polarity in T cell contacts. Cell 94, 667–677 4 Grakoui, A. et al. (1999) The immunological synapse: A molecular machine controlling T cell activation. Science 285, 221–227 5 Iezzi, G. et al. (1998) The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 6 Bromley, S.K. et al. (2000) Cutting Edge: Hierarchy of Chemokine Receptor and TCR Signals Regulating T Cell Migration and Proliferation. J. Immunol. 165, 15–19 phagocytosis or target cells for cytotoxicity. This serial encounter process serves to amplify the response, particularly for less-abundant CD4+ T cells. The IS model can incorporate the new data on dominant chemokines and collagen regulation of IS formation to provide insights into the multiple signals required to orchestrate T-cell-dependent immune responses. 7 Gunzer, M. et al. (2000) Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13, 323–332 8 Lanzavecchia, A. and Sallusto, F. (2000) Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science 290, 92–97 9 Friedl, P. and Gunzer, M. (2001) Interaction of T cells with APCs: the serial encounter model. Trends Immunol. 22, 187–191 10 Martz, E. (1987) LFA-1 and other accessory molecules functioning in adhesions of T and B lymphocytes. Human Immunol. 18, 3–37 11 Maniotis, A.J. et al. (1997) Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc. Natl. Acad. Sci. U. S. A. 94, 849–854 12 Miyamoto, S. et al. (1996) Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and Tapasin: an ER chaperone that controls MHC class I assembly with peptide Andres G. Grandea III and Luc Van Kaer The stable assembly of MHC class I molecules with peptides in the endoplasmic reticulum (ER) involves several accessory molecules. One of these accessory molecules is tapasin, a transmembrane protein that tethers empty class I molecules to the peptide transporter associated with antigen processing (TAP). Here, evidence is presented that tapasin retains class I molecules in the ER until they acquire high-affinity peptides. MHC class I molecules present peptides, usually eight or nine amino acids in length, to CD8-expressing cytotoxic T lymphocytes (CTLs). Most peptides that bind class I molecules are derived from newly 13 14 15 16 17 18 MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J. Cell Biol. 135, 1633–1642 Turley, S.J. et al. (2000) Transport of peptideMHC class II complexes in developing dendritic cells. Science 288, 522–527 Ebnet, K. et al. (1996) Orchestrated information transfer underlying leukocyte endothelial interactions. Annu. Rev. Immunol. 14, 155–177 Campbell, J.J. et al. (1998) Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 Ingulli, E. et al. (1997) In vivo detection of dendritic cell antigen presentation to CD4(+) T cells. J. Exp. Med. 185, 2133–2141 Svoboda, K. et al. (1997) In vivo dendritic calcium dynamics in neocortical pyramidal neurons. Nature 385, 161–165 Garside, P. et al. (1998) Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 synthesized proteins in the cytosol1. Such proteins are subject to limited degradation by large proteolytic complexes termed proteasomes (Fig. 1). A subset of the resulting peptides are translocated across the endoplasmic reticulum (ER) membrane by the peptide transporter associated with antigen processing (TAP), and are loaded onto peptide-receptive MHC class I molecules in the ER. Peptide-loaded class I molecules are then transported to the cell surface for recognition by class I-restricted CTLs. This antigen presentation pathway is critically important for immune surveillance against viruses and tumors. The loading of MHC class I molecules with peptides in the ER is facilitated by several accessory molecules, including proteins with general housekeeping functions and the dedicated chaperone tapasin1–4. Although tapasin appears to play an important role in the quality control of MHC class I assembly, its precise function remains controversial. Here, it is proposed that tapasin retains class I molecules in the ER until optimal ligand selection is completed. Role of general housekeeping proteins in class I assembly Shortly after their synthesis, MHC class I heavy chains associate with the ER-resident chaperone calnexin1 (Fig. 1). In human cells, binding of class I heavy chains to β2-microglobulin (β2-m) results in the exchange of calnexin for the chaperone calreticulin; http://immunology.trends.com 1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)01861-0