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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

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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. Furthermore, PI3K inhibitors naling molecules in the cSMAC boosts cates with the TCR to the cSMAC upon blocked RhoG-GTP formation without T cell activation. However, observations T cell activation (Delgado et al., 2009). affecting TC21 activation. This led the that the cSMAC forms after the peak Expression of either inactive or constitu- authors to propose a novel signaling path- of protein tyrosine phosphorylation has tively active TC21 mutants inhibited TCR way in which TC21, which directly binds to been reached and is enriched in ubiquitin internalization from the cSMAC, indicating the TCR and activates the p110d-isoform ligases and ubiquitinylated proteins sug- that conversion between the GDP- and of PI3K (Delgado et al., 2009), is upstream gested a role in TCR internalization and GTP-bound forms of TC21 is crucial for of RhoG. Activated RhoG in turn promotes degradation, and thus, in the termination this process. Moreover, TC21 and the actin polymerization, which is required of signaling. Another layer of complexity TCR colocalized in clathrin-deficient intra- for trogocytosis (Figure 1).

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Although the current view is that TCR responses, helping to characterize the that feed from their victims without killing internalization dampens signaling by re- stimulatory or suppressive effects that them. moving the antigen and promoting re- have been attributed to trogocytosis. T ceptor degradation, internalization of a helper cells that have captured pMHC via REFERENCES pMHC-TCR complex by trogocytosis trogocytosis can present these pMHC opens new questions. Is internalization complexes to other T cells, amplifying an Bell, G.I. (1978). Science 200, 618–627. by trogocytosis a way to prolong the immune response. Cytotoxic T cells (CTLs) Cemerski, S., Das, J., Giurisato, E., Markiewicz, TCR-pMHC interaction even after APC that have captured agonistic pMHC by tro- M.A., Allen, P.M., Chakraborty, A.K., and Shaw, separation? Are those TCRs still signaling gocytosis become susceptible to cytolysis A.S. (2008). Immunity 29, 414–422. competent? In this regard, RhoG- or by neighboring CTLs, which could result Cone, R.E., Sprent, J., and Marchalonis, J.J. TC21-deficient T cells stimulated by in a dampening of an immune response. (1972). Proc. Natl. Acad. Sci. USA 69, 2556–2560. APCs showed increased upregulation of While trying to understand the purpose Delgado, P., Cubelos, B., Calleja, E., Martı´nez- early TCR-mediated activation markers, and consequences of trogocytosis, ener- Martı´n, N., Cipre´ s, A., Me´ rida, I., Bellas, C., Bus- such as CD69. This could suggest that getic concerns arise: how do T cells telo, X.R., and Alarco´ n, B. (2009). Nat. Immunol. 10, 880–888. signaling of TCRs from the cell surface generate the force needed to tear off is required to stimulate TC21- and the APC-membrane patch containing Henson, P.M. (2005). Curr. Biol. 15, R29–R30. RhoG-independent signaling cascades pMHC? The force required to pull a protein Joly, E., and Hudrisier, D. (2003). Nat. Immunol. 4, that upregulate CD69. In contrast, T cell and surrounding lipids from a membrane 815. proliferation was reduced in RhoG- or is on the same order of magnitude as Liu, H., Rhodes, M., Wiest, D.L., and Vignali, D.A. TC21-deficient T cells, either suggesting the force needed to break a high-affinity (2000). Immunity 13, 665–675. that trogocytosed TCRs are required to protein-protein interaction (Bell, 1978). Martı´nez-Martı´n, N., Fernandez-Arenas, E., stimulate proliferation or that RhoG and Therefore, trogocytosis could be energet- Cemerski, S., Delgado, P., Turner, M., Heuser, J., TC21 are involved in the signaling path- ically beneficial for the T cell, given that Irvine, D., Huang, B., Bustelo, X., Shaw, A.S., and Alarcon, B. (2011). Immunity 35, this issue, ways that promote proliferation. the acquired lipids could be recycled or 208–222. Taken together, these data open novel metabolized. This might increase the possibilities to study the functional conse- capacity of the T cell to proliferate. Monjas, A. (2004). J. Biol. Chem. 279, 55376– 55384. quences of trogocytosis. Lineage-specific In that sense, T cells that are blood cells deletion of RhoG could be useful to study themselves and take up protein com- Schamel, W.W., Arechaga, I., Risueno, R.M., van Santen, H.M., Cabezas, P., Risco, C., Val- the contribution of trogocytosis in differ- plexes in membrane ‘‘bites’’ from other puesta, J.M., and Alarcon, B. (2005). J. Exp. ent cell types in the course of immune cells could be fancied as little vampires Med. 202, 493–503.

Intracellular Pathogens and CD8+ Dendritic Cells: Dangerous Liaisons

Boris Reizis1,* 1Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA *Correspondence: [email protected] DOI 10.1016/j.immuni.2011.08.003

CD8+ dendritic cells comprise a distinct cell type whose function is unclear. In this issue of Immunity, Mashayekhi et al. (2011) show these cells are essential for protection against the parasite Toxoplasma,but Edelson et al. (2011) show they are hijacked by Listeria during initial spreading.

Dendritic cells (DCs) are a distinct lineage lymphoid organs but also in tissues, in has been identified in humans, with this of mononuclear phagocytes that excel which CD103+ DCs represent a genetic conservation probably reflecting an es- at pathogen sensing, cytokine secretion, and functional equivalent of CD8+ DCs. sential role in immunity. An overwhelming and antigen presentation. The classical Notably, CD8+ and CD103+ DCs are body of evidence suggests that CD8+ DCs comprise two distinct subsets, dis- found in relatively low numbers in vivo DCs are particularly efficient at cross-pre- tinguished in the mouse by the expression (0.1%–0.2% of murine splenocytes), to sentation, i.e., the presentation of exoge- of CD8a (Shortman and Heath, 2010). the dismay of researchers who study nously acquired antigens on MHC class I This subset dichotomy exists not only in them. A DC subset similar to CD8+ DCs molecules to CD8+ T cells. Although this

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