View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity Previews protect against severe disease. This is type I IFNs in malaria infection. The pres- Herbich, K., Schmid, D., et al. (2000). Infect. Immun. consistent with the finding that recombi- ence of AT-rich motifs in the genomes of 68, 3909–3915. nant IFN-a administration early in PbA other protozoa, bacteria, and humans Parroche, P., Lauw, F.N., Goutagny, N., Latz, E., infection reduced parasitemia and pro- suggests that these motifs could con- Monks, B.G., Visintin, A., Halmen, K.A., Lamphier, M., Olivier, M., Bartholomeu, D.C., et al. (2007). tected against ECM in a IFN-g-dependent tribute to the pathogenesis of other Proc. Natl. Acad. Sci. USA 104, 1919–1924. manner (Vigario et al., 2007). A beneficial severe infectious syndromes. In the case effect of type I IFNs was also suggested of extracellular DNA sources, it is in- Sharma, S., DeOliveira, R.B., Kalantari, P., Parroche, P., Goutagny, N., Jiang, Z., Chan, J., by higher plasma IFN-a levels in African triguing to consider that other crystals Bartholomeu, D.C., Lauw, F., Hall, J.P., et al. children with mild malaria compared to (e.g., urate) may move these motifs into (2011). Immunity 35, this issue, 194–207. those with hyperparasitemia or severe the cytosol for innate sensing. This pro- Shimosato, T., Kimura, T., Tohno, M., Iliev, I.D., malarial anemia (Luty et al., 2000). The posed mechanism, if confirmed, may Katoh, S., Ito, Y., Kawai, Y., Sasaki, T., Saito, T., heterogeneity and complexity of human have relevance for the development of and Kitazawa, H. (2006). Cell. Microbiol. 8, severe malaria necessitate examining DNA-based vaccine adjuvants. 485–495. the role of type I IFNs in diverse patient Shio, M.T., Eisenbarth, S.C., Savaria, M., Vinet, populations and in multiple murine A.F., Bellemare, M.J., Harder, K.W., Sutterwala, REFERENCES F.S., Bohle, D.S., Descoteaux, A., Flavell, R.A., models representing different aspects of and Olivier, M. (2009). PLoS Pathog. 5, e1000559. human disease. However, the present findings do caution against administration Coban, C., Ishii, K.J., Kawai, T., Hemmi, H., Sato, van der Heyde, H.C., Nolan, J., Combes, V., S., Uematsu, S., Yamamoto, M., Takeuchi, O., Gramaglia, I., and Grau, G.E. (2006). Trends of type I IFNs as adjunctive therapy for Itagaki, S., Kumar, N., et al. (2005). J. Exp. Med. Parasitol. 22, 503–508. CM, especially because patients typically 201, 19–25. present with advanced pathology. Vigario, A.M., Belnoue, E., Gruner, A.C., Mauduit, Lovegrove, F.E., Gharib, S.A., Patel, S.N., Hawkes, M., Kayibanda, M., Deschemin, J.C., Marussig, In summary, Sharma et al. (2011) C.A., Kain, K.C., and Liles, W.C. (2007). Am. J. M., Snounou, G., Mazier, D., Gresser, I., and Renia, identify a unique cytosolic DNA sensing Pathol. 171, 1894–1903. L. (2007). J. Immunol. 178, 6416–6425. pathway and considerably expand our Luty, A.J., Perkins, D.J., Lell, B., Schmidt-Ott, R., Wu, X., Gowda, N.M., Kumar, S., and Gowda, D.C. knowledge of the induction and role of Lehman, L.G., Luckner, D., Greve, B., Matousek, P., (2010). J. Immunol. 184, 4338–4348. A New Vampire Saga: The Molecular Mechanism of T Cell Trogocytosis Elaine Pashupati Dopfer,1 Susana Minguet,1 and Wolfgang W.A. Schamel1,* 1Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signalling Studies, Center for Chronic Immunodeficiency (CCI) and Max-Planck-Institute for Immunbiology and Epigenetics, Stu¨ beweg 51, 79108 Freiburg, Germany *Correspondence: [email protected] DOI 10.1016/j.immuni.2011.08.004 In the current issue of Immunity, Martı´nez-Martı´n et al. (2011) 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 senting cell (APC) to a lymphocyte (Joly in vitro and in vivo. Trogocytosis can be the orchestration of the immune system and Hudrisier, 2003). This is in strong distinguished from other mechanisms of and its responses. Although immune cells contrast to phagocytosis, the process of intercellular transfer because it requires normally communicate through either engulfing whole pathogens and death close cell-cell contact, is quick (within soluble or membrane-bound mediators, cell fragments by phagocytes. minutes), and involves transfer of intact new types of cellular interchange have The first evidence of trogocytosis was proteins. Previous studies focused on the been described, including trogocytosis, the transfer of major histocompatibility celltypes involvedand the molecules trans- exosome secretion, and nanotube forma- complex class II (MHCII) glycoproteins ferred, but the molecular mechanism that tion. The term trogocytosis (from Greek from B to T cells (Cone et al., 1972). Since underpins this phenomenon has remained trogo-, nibble) was originally coined to then, trogocytotic activity has been re- largely unknown. Trogocytosis is an active describe the intercellular transfer of ported for T, B, natural killer (NK), and process in T and NK cells, requiring both membrane patches from an antigen-pre- dendritic cells and is well documented receptor signaling and actin cytoskeleton Immunity 35, August 26, 2011 ª2011 Elsevier Inc. 151 Immunity Previews MHCp APC cellular vesicles, and shRNA-mediated TCR silencing of clathrin did not affect TCR nanocluster and TC21 cointernalization. The authors Re-expression TCR also have shown by electron microscopy T cell microcluster that, in contrast to the pSMAC, the cSMAC is devoid of clathrin-coated pits. Clathrin Altogether, the authors propose a model Signal in which triggered TCRs are internalized TC21 PI3K Trogocytosis at the cSMAC by a TC21-dependent RhoG but clathrin-independent mechanism. In Actin contrast, homeostatic clathrin-mediated internalization might take place in the Degradation pSMAC cSMAC Signal Degradation pSMAC. Additionally, RhoG was identified as a Figure 1. TCR Internalization and Trogocytosis in T Cells player in TC21-dependent TCR internali- Constitutive TCR turnover occurs in resting cells. Upon stimulation, TCR nanoclusters aggregate to zation. Like TC21, RhoG must cycle be- signaling-active microclusters that can be internalized in the pSMAC in a clathrin-dependent manner. tween active and inactive conformations Once the microclusters have reached the cSMAC, patches of the APC containing the pMHC molecules are trogocytosed with a TC21- and RhoG-dependent mechanism. Trogocytosed membrane proteins to promote TCR internalization from the from the APC can be re-expressed on the T cell. cSMAC. Because RhoG was first de- scribed in the phagocytosis of apoptotic bodies (Henson, 2005), the authors inves- remodeling. In this issue of Immunity,the was added when analyzing ligands of tigated the capability of T cells to phago- group of Balbino Alarco´ nprovidesnew different qualities, given that the cSMAC cytose anti-TCR-coupled latex beads. It insights into the molecular mechanism can enhance stimulation by weak agonists was surprising that primary T cells were that drives T cell antigen receptor (TCR)- (Cemerski et al., 2008). TCR stimulation by able to phagocytose beads that were as mediated trogocytosis by identifying the pMHC leads to TCR downmodulation, big as themselves, which they accommo- small GTPases TC21 and RhoG as key mainly by increasing TCR degradation, dated through massive reorganization of players (Martı´nez-Martı´n et al., 2011). because clathrin-mediated TCR endocy- their cytoplasm and plasma membrane. On resting T cells, the TCR coexists in tosis is unchanged (Liu et al., 2000). How- TCR-driven phagocytosis of beads was monomeric and nanoclustered forms ever, intense TCR stimulation leads to impaired in T lymphocytes derived from (Schamel et al., 2005). The amount of marginal acceleration of TCR internaliza- TC21- or RhoG-deficient mice when TCR expressed on the cell surface is tion by a second, clathrin-independent compared to wild-type controls. In stimu- tightly controlled by the rates of TCR pathway (Monjas, 2004). Yet, detailed lated T cells from TC21- and RhoG-defi- synthesis, constitutive clathrin-mediated insight into when and where clathrin- cient mice, total downregulation of the TCR internalization, recycling and degra- dependent or -independent internalization TCR was only slightly affected, suggest- dation (Figure 1). Once the T cell is stimu- occurs is still missing. ing that clathrin-mediated internalization lated by antigenic peptides presented on In the present article, Martı´nez-Martı´n was prominent. In contrast, acquisition MHC (pMHC), the TCRs aggregate to et al. identify the cSMAC as the site of of membrane patches and MHC mole- form microclusters. These pMHC-in- clathrin-independent TCR internalization cules by trogocytosis was greatly de- duced microclusters contain phosphory- and report that together with the inter- creased in CD4+ and CD8+ T cells. lated TCRs that initiate activation of the nalized TCR, membrane patches and Further, acquisition of membrane patches cell. Subsequently, the microclusters coa- pMHC complexes from the APC are and TCR-triggered phagocytosis were lesce to form the central supramolecular trogocytosed. actin dependent and probably equivalent activation cluster (cSMAC) surrounded Using time-lapse confocal videomicro- phenomena. by the peripheral SMAC (pSMAC), to- scopy and primary T cells derived from Using pharmacological inhibitors, gether forming an immune synapse. The genetically ablated mice, they have shown Martı´nez-Martı´n et al. showed that inacti- functional significance of the cSMAC has that TCR internalization from the cSMAC vation of phosphatidyl inositol-3 kinase been the subject of recent controversy. is dependent on the small GTPases (PI3K) reduced the phagocytosis of beads Originally, it had been proposed that accu- TC21 and RhoG. TC21 is constitutively as well as membrane acquisition by mulation of engaged receptors and sig- associated with the TCR and co-translo- trogocytosis.