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• W1999184001 abstract "In the current issue of Immunity, Martínez-Martín et al., 2011Martínez-Martín N. Fernandez-Arenas E. Cemerski S. Delgado P. Turner M. Heuser J. Irvine D. Huang B. Bustelo X. Shaw A.S. Alarcon B. Immunity. 2011; 35 (this issue): 208-222Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar describe the central supramolecular activation cluster (cSMAC) as a site of clathrin-independent T cell receptor (TCR) internalization and trogocytosis. Further, they identify small Rho GTPases TC21 and RhoG as key mediators of these processes. In the current issue of Immunity, Martínez-Martín et al., 2011Martínez-Martín N. Fernandez-Arenas E. Cemerski S. Delgado P. Turner M. Heuser J. Irvine D. Huang B. Bustelo X. Shaw A.S. Alarcon B. Immunity. 2011; 35 (this issue): 208-222Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar describe the central supramolecular activation cluster (cSMAC) as a site of clathrin-independent T cell receptor (TCR) internalization and trogocytosis. Further, they identify small Rho GTPases TC21 and RhoG as key mediators of these processes. Cell-to-cell communication is essential for the orchestration of the immune system and its responses. Although immune cells normally communicate through either soluble or membrane-bound mediators, new types of cellular interchange have been described, including trogocytosis, exosome secretion, and nanotube formation. The term trogocytosis (from Greek trogo-, nibble) was originally coined to describe the intercellular transfer of membrane patches from an antigen-presenting cell (APC) to a lymphocyte (Joly and Hudrisier, 2003Joly E. Hudrisier D. Nat. Immunol. 2003; 4: 815Crossref PubMed Scopus (333) Google Scholar). This is in strong contrast to phagocytosis, the process of engulfing whole pathogens and death cell fragments by phagocytes. The first evidence of trogocytosis was the transfer of major histocompatibility complex class II (MHCII) glycoproteins from B to T cells (Cone et al., 1972Cone R.E. Sprent J. Marchalonis J.J. Proc. Natl. Acad. Sci. USA. 1972; 69: 2556-2560Crossref PubMed Scopus (50) Google Scholar). Since then, trogocytotic activity has been reported for T, B, natural killer (NK), and dendritic cells and is well documented in vitro and in vivo. Trogocytosis can be distinguished from other mechanisms of intercellular transfer because it requires close cell-cell contact, is quick (within minutes), and involves transfer of intact proteins. Previous studies focused on the cell types involved and the molecules transferred, but the molecular mechanism that underpins this phenomenon has remained largely unknown. Trogocytosis is an active process in T and NK cells, requiring both receptor signaling and actin cytoskeleton remodeling. In this issue of Immunity, the group of Balbino Alarcón provides new insights into the molecular mechanism that drives T cell antigen receptor (TCR)-mediated trogocytosis by identifying the small GTPases TC21 and RhoG as key players (Martínez-Martín et al., 2011Martínez-Martín N. Fernandez-Arenas E. Cemerski S. Delgado P. Turner M. Heuser J. Irvine D. Huang B. Bustelo X. Shaw A.S. Alarcon B. Immunity. 2011; 35 (this issue): 208-222Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). On resting T cells, the TCR coexists in monomeric and nanoclustered forms (Schamel et al., 2005Schamel W.W. Arechaga I. Risueno R.M. van Santen H.M. Cabezas P. Risco C. Valpuesta J.M. Alarcon B. J. Exp. Med. 2005; 202: 493-503Crossref PubMed Scopus (229) Google Scholar). The amount of TCR expressed on the cell surface is tightly controlled by the rates of TCR synthesis, constitutive clathrin-mediated TCR internalization, recycling and degradation (Figure 1). Once the T cell is stimulated by antigenic peptides presented on MHC (pMHC), the TCRs aggregate to form microclusters. These pMHC-induced microclusters contain phosphorylated TCRs that initiate activation of the cell. Subsequently, the microclusters coalesce to form the central supramolecular activation cluster (cSMAC) surrounded by the peripheral SMAC (pSMAC), together forming an immune synapse. The functional significance of the cSMAC has been the subject of recent controversy. Originally, it had been proposed that accumulation of engaged receptors and signaling molecules in the cSMAC boosts T cell activation. However, observations that the cSMAC forms after the peak of protein tyrosine phosphorylation has been reached and is enriched in ubiquitin ligases and ubiquitinylated proteins suggested a role in TCR internalization and degradation, and thus, in the termination of signaling. Another layer of complexity was added when analyzing ligands of different qualities, given that the cSMAC can enhance stimulation by weak agonists (Cemerski et al., 2008Cemerski S. Das J. Giurisato E. Markiewicz M.A. Allen P.M. Chakraborty A.K. Shaw A.S. Immunity. 2008; 29: 414-422Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). TCR stimulation by pMHC leads to TCR downmodulation, mainly by increasing TCR degradation, because clathrin-mediated TCR endocytosis is unchanged (Liu et al., 2000Liu H. Rhodes M. Wiest D.L. Vignali D.A. Immunity. 2000; 13: 665-675Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). However, intense TCR stimulation leads to marginal acceleration of TCR internalization by a second, clathrin-independent pathway (Monjas, 2004Monjas A. J. Biol. Chem. 2004; 279: 55376-55384Crossref PubMed Scopus (42) Google Scholar). Yet, detailed insight into when and where clathrin-dependent or -independent internalization occurs is still missing. In the present article, Martínez-Martín et al. identify the cSMAC as the site of clathrin-independent TCR internalization and report that together with the internalized TCR, membrane patches and pMHC complexes from the APC are trogocytosed. Using time-lapse confocal videomicroscopy and primary T cells derived from genetically ablated mice, they have shown that TCR internalization from the cSMAC is dependent on the small GTPases TC21 and RhoG. TC21 is constitutively associated with the TCR and co-translocates with the TCR to the cSMAC upon T cell activation (Delgado et al., 2009Delgado P. Cubelos B. Calleja E. Martínez-Martín N. Ciprés A. Mérida I. Bellas C. Bustelo X.R. Alarcón B. Nat. Immunol. 2009; 10: 880-888Crossref PubMed Scopus (85) Google Scholar). Expression of either inactive or constitutively active TC21 mutants inhibited TCR internalization from the cSMAC, indicating that conversion between the GDP- and GTP-bound forms of TC21 is crucial for this process. Moreover, TC21 and the TCR colocalized in clathrin-deficient intracellular vesicles, and shRNA-mediated silencing of clathrin did not affect TCR and TC21 cointernalization. The authors also have shown by electron microscopy that, in contrast to the pSMAC, the cSMAC is devoid of clathrin-coated pits. Altogether, the authors propose a model in which triggered TCRs are internalized at the cSMAC by a TC21-dependent but clathrin-independent mechanism. In contrast, homeostatic clathrin-mediated internalization might take place in the pSMAC. Additionally, RhoG was identified as a player in TC21-dependent TCR internalization. Like TC21, RhoG must cycle between active and inactive conformations to promote TCR internalization from the cSMAC. Because RhoG was first described in the phagocytosis of apoptotic bodies (Henson, 2005Henson P.M. Curr. Biol. 2005; 15: R29-R30Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), the authors investigated the capability of T cells to phagocytose anti-TCR-coupled latex beads. It was surprising that primary T cells were able to phagocytose beads that were as big as themselves, which they accommodated through massive reorganization of their cytoplasm and plasma membrane. TCR-driven phagocytosis of beads was impaired in T lymphocytes derived from TC21- or RhoG-deficient mice when compared to wild-type controls. In stimulated T cells from TC21- and RhoG-deficient mice, total downregulation of the TCR was only slightly affected, suggesting that clathrin-mediated internalization was prominent. In contrast, acquisition of membrane patches and MHC molecules by trogocytosis was greatly decreased in CD4+ and CD8+ T cells. Further, acquisition of membrane patches and TCR-triggered phagocytosis were actin dependent and probably equivalent phenomena. Using pharmacological inhibitors, Martínez-Martín et al. showed that inactivation of phosphatidyl inositol-3 kinase (PI3K) reduced the phagocytosis of beads as well as membrane acquisition by trogocytosis. Furthermore, PI3K inhibitors blocked RhoG-GTP formation without affecting TC21 activation. This led the authors to propose a novel signaling pathway in which TC21, which directly binds to the TCR and activates the p110δ-isoform of PI3K (Delgado et al., 2009Delgado P. Cubelos B. Calleja E. Martínez-Martín N. Ciprés A. Mérida I. Bellas C. Bustelo X.R. Alarcón B. Nat. Immunol. 2009; 10: 880-888Crossref PubMed Scopus (85) Google Scholar), is upstream of RhoG. Activated RhoG in turn promotes actin polymerization, which is required for trogocytosis (Figure 1). Although the current view is that TCR internalization dampens signaling by removing the antigen and promoting receptor degradation, internalization of a pMHC-TCR complex by trogocytosis opens new questions. Is internalization by trogocytosis a way to prolong the TCR-pMHC interaction even after APC separation? Are those TCRs still signaling competent? In this regard, RhoG- or TC21-deficient T cells stimulated by APCs showed increased upregulation of early TCR-mediated activation markers, such as CD69. This could suggest that signaling of TCRs from the cell surface is required to stimulate TC21- and RhoG-independent signaling cascades that upregulate CD69. In contrast, T cell proliferation was reduced in RhoG- or TC21-deficient T cells, either suggesting that trogocytosed TCRs are required to stimulate proliferation or that RhoG and TC21 are involved in the signaling pathways that promote proliferation. Taken together, these data open novel possibilities to study the functional consequences of trogocytosis. Lineage-specific deletion of RhoG could be useful to study the contribution of trogocytosis in different cell types in the course of immune responses, helping to characterize the stimulatory or suppressive effects that have been attributed to trogocytosis. T helper cells that have captured pMHC via trogocytosis can present these pMHC complexes to other T cells, amplifying an immune response. Cytotoxic T cells (CTLs) that have captured agonistic pMHC by trogocytosis become susceptible to cytolysis by neighboring CTLs, which could result in a dampening of an immune response. While trying to understand the purpose and consequences of trogocytosis, energetic concerns arise: how do T cells generate the force needed to tear off the APC-membrane patch containing pMHC? The force required to pull a protein and surrounding lipids from a membrane is on the same order of magnitude as the force needed to break a high-affinity protein-protein interaction (Bell, 1978Bell G.I. Science. 1978; 200: 618-627Crossref PubMed Scopus (3165) Google Scholar). Therefore, trogocytosis could be energetically beneficial for the T cell, given that the acquired lipids could be recycled or metabolized. This might increase the capacity of the T cell to proliferate. In that sense, T cells that are blood cells themselves and take up protein complexes in membrane “bites” from other cells could be fancied as little vampires that feed from their victims without killing them. T Cell Receptor Internalization from the Immunological Synapse Is Mediated by TC21 and RhoG GTPase-Dependent PhagocytosisMartínez-Martín et al.ImmunityAugust 4, 2011In BriefThe immunological synapse (IS) serves a dual role for sustained T cell receptor (TCR) signaling and for TCR downregulation. TC21 (Rras2) is a RRas subfamily GTPase that constitutively associates with the TCR and is implicated in tonic TCR signaling by activating phosphatidylinositol 3-kinase. In this study, we demonstrate that TC21 both cotranslocates with the TCR to the IS and is necessary for TCR internalization from the IS through a mechanism dependent on RhoG, a small GTPase previously associated with phagocytosis. Full-Text PDF Open Archive" @default.
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• W1999184001 title "A New Vampire Saga: The Molecular Mechanism of T Cell Trogocytosis" @default.
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