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An Initial and Rapid Step of Lytic Granule Secretion Precedes Microtubule Organizing Center Polarization at the Cytotoxic T Lymphocyte/Target Cell Synapse

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An Initial and Rapid Step of Lytic Granule Secretion Precedes Microtubule Organizing Center Polarization at the Cytotoxic T Lymphocyte/Target Cell Synapse An initial and rapid step of lytic granule secretion precedes microtubule organizing center polarization at the cytotoxic T lymphocyte/target cell synapse Florie Bertranda,b,c,1, Sabina Müllera,b,c,1, Kyung-Ho Rohd,e, Camille Laurenta,b,c, Loïc Dupréa,b,c, and Salvatore Valituttia,b,c,2 aSection Dynamique Moléculaire des Interactions Lymphocytaires, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1043, Centre de Physiopathologie de Toulouse Purpan, 31024 Toulouse, France; bUniversité Toulouse III Paul-Sabatier, 31062 Toulouse, France; cLaboratoire d’Excellence Toulouse Cancer, Toulouse, France; and dDepartment of Microbiology and Immunology, and eHoward Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5323 Edited by Mark M. Davis, Stanford University School of Medicine, Stanford, CA, and approved March 5, 2013 (received for review November 1, 2012) It is presently assumed that lethal hit delivery by cytotoxic T (MTOC) and the centrosome beneath the IS and by a microtubule lymphocytes (CTLs) is mechanistically linked to centrosome polari- cytoskeleton–directed movement of lytic granules toward the target zation toward target cells, leading to dedicated release of lytic cells. These observations suggest a mechanistic link between cen- granules within a confined secretory domain. Here we provide three trosome docking to the plasma membrane and lytic granule se- lines of evidence showing that this mechanism might not apply as cretion (11, 12). Such a mechanism is considered instrumental to a general paradigm for lethal hit delivery. First, in CTLs stimulated ensure confined secretion of lytic molecules within the synaptic with immobilized peptide–MHC complexes, lytic granules and mi- cleft, resulting in selective killing of cognate target cells (1). crotubule organizing center localization into synaptic areas are spa- Although parallel movement of lytic granules and MTOC to- tio-temporally dissociated, as detected by total internal reflection ward the IS has been thoroughly documented, whether a mech- fluorescence microscopy. Second, in many CTL/target cell conju- anistic link exists between MTOC polarization and lytic granule gates, lytic granule secretion precedes microtubule polarization secretion is still unknown. In particular, it is not clear whether and can be detected during the first minute after cell–cell contact. lytic granule secretion is initiated at the CTL/target cell contact IMMUNOLOGY Third, inhibition of microtubule organizing center and centrosome site immediately after a cell–cell encounter, independently of polarization impairs neither lytic granule release at the CTL synapse MTOC repolarization. nor killing efficiency. Our results broaden current views of CTL bi- In the present study performed with untransformed human ology by revealing an extremely rapid step of lytic granule secretion CTLs, we show that lytic granule enrichment at the synaptic area and by showing that microtubule organizing center polarization is and their secretion precede MTOC polarization in ∼50% of the fi dispensable for ef cient lethal hit delivery. analyzed CTLs, as detected by total internal reflection fluorescence microscopy (TIRFM) and time-lapse microscopy. In addition, se- ζ immunological synapse | T-cell antigen receptor | protein kinase C | lective inhibition of MTOC/centrosome polarization inhibited signal transduction neither lytic granule secretion at the IS nor cytotoxic activity. Taken together, our results show that CTLs can secrete lytic ytotoxic T lymphocytes (CTLs) are central actors of the granules at the synaptic area as early as 40–60 s after target cell Cadaptive immune response implicated in the elimination of encounter and before MTOC polarization. They also show that infected cells and tumor cells. On encounter with cognate target lytic granule secretion can occur in conditions in which MTOC cells, CTLs activate different cytotoxic mechanisms, leading to polarization is inhibited. These unexpectedly rapid and MTOC- target cell annihilation. Among those mechanisms, the most rapid independent secretory events provide a basis for the described and efficient pathway of CTL-mediated cytotoxicity is the release capacity of CTL to behave as multiple killers of different target of the pore-forming protein perforin together with granzymes and cells encountered simultaneously. other proteolytic enzymes (all stored in cytosolic granules, named lytic granules) at the CTL/target cell immunological synapse (IS) Results (1–3). In human CTL and natural killer (NK) cells, the perforin/ Monitoring MTOC and Lytic Granule Dynamics in Antigen-Stimulated granzyme pathway plays a central role in immune surveillance, as CTLs. To study the dynamics of lytic granules and of the MTOC indicated by the severe immunodeficiency phenotype of patients within the IS area, we first used TIRFM to restrict the spatial exhibiting genetic mutations of perforin or of molecules implicated window of observation within a few hundred nanometers proxi- in lytic granule docking and fusion to plasma membrane (4). mal to the IS. HLA-A2–restricted human CTLs specific for the Cytotoxicity is a highly dynamic phenomenon, based on the CMV pp65 peptide were loaded with LysoTracker-red and formation of rapid and multiple cellular contacts. CTL have been TubulinTracker-green to monitor in parallel lytic granules and shown to kill target cells displaying on their surface extremely low microtubule dynamics and were then seeded into microchambers antigen densities within a few minutes after initial contact (5–9). Moreover, CTL have been reported to kill multiple target cells either serially, by bouncing from one target to another, or simul- Author contributions: F.B., S.M., and S.V. designed research; F.B., S.M., K.-H.R., and C.L. taneously (9, 10). performed research; F.B., S.M., and S.V. analyzed data; and F.B., S.M., L.D., and S.V. wrote Despite detailed knowledge of the immunological function of the paper. CTLs and of the numerous molecular steps involved in the re- The authors declare no conflict of interest. lease of lytic granule content after T-cell antigen receptor (TCR) This article is a PNAS Direct Submission. engagement, we do not have a complete understanding of the Freely available online through the PNAS open access option. process of lytic granule secretion at the CTL/target cell IS. 1F.B. and S.M. contributed equally to this work. The established model of CTL-mediated cytotoxicity is based 2To whom correspondence should be addressed. E-mail: [email protected]. on the observations that lethal hit delivery to target cells is par- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. alleled by the repositioning of the microtubule-organizing center 1073/pnas.1218640110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1218640110 PNAS Early Edition | 1of6 Downloaded by guest on September 24, 2021 2+ coated with specific peptide-MHC complexes (pMHCs). In CTLs 45% of CTL/target cell conjugates, [Ca ]i increase in target cells stimulated by immobilized specific pMHCs, lytic granules were was detected simultaneously with CTL MTOC polarization (32 of 2+ detected in the TIRF plane during the entire time of acquisition (a 72 cells scored). Conversely, in 55% of the conjugates, [Ca ]i total of 59 CTLs were scored for 180–360 s). On the contrary, increase preceded CTL MTOC polarization at the synaptic area MTOC was detected much less frequently in the TIRF plane. (40 of 72 cells scored; Fig. 2B; Movies S11 and S12). Fig. 2C shows fi 2+ Indeed, depending on the cells analyzed, we identi ed different the comparison of the time required for [Ca ]i increase in target types of MTOC dynamics: (i) MTOC did not appear in the TIRF cells and for CTL MTOC polarization in typical CTL/target cell plane (18 cells, 30% of total, Fig. 1A; Movie S1); (ii) microtubules conjugates exhibiting the latter phenotype. This single cell analysis 2+ and lytic granules appeared almost simultaneously, yet MTOC was showed that in these CTL/target cell conjugates, [Ca ]i increase detected in the TIRF plane later than lytic granules and stayed in clearly preceded MTOC polarization of the conjugated CTLs. B 2+ that plane only very transiently (24 cells, 41% of total; Fig. 1 ; [Ca ]i increase in target cells could be detected as early as a few Movie S2); (iii) MTOC appeared at the beginning of the movie but tens of seconds after initial CTL/target cell contact (Fig. 2C). then disappeared from the TIRF plane, whereas lytic granules Taken together these results show that lytic granule dynamics stayed in that plane for all of the acquisition time (7 cells, 12% of and secretion in antigen-stimulated CTLs does not coincide with total; Fig. 1C; Movie S3); and (iv) microtubules with or without MTOC dynamics and that lytic granule secretion can be initiated a distinguishable MTOC structure were detected in the TIRF before MTOC polarization. plane at the beginning of the acquisition and disappeared during the acquisition (10 cells, 17% of total; Fig. 1D; Movie S4). In cells Lytic Granule Secretion by CTLs Can Occur in the Absence of Detectable in which MTOC was clearly detectable in the TIRF plane, al- MTOC Synaptic Recruitment. We next attempted to prevent CTL though lytic granules could be observed in close proximity of the MTOC polarization to extend the window of time whereby MTOC- MTOC, they were frequently spread in the entire TIRF plane and independent lytic granule dynamics could be observed. To do so, found up to 5 μm away from the MTOC. Control experiments we targeted protein kinase Cζ (PKCζ) function in CTLs. Indeed, showed that, under the above-described conditions, CTLs were we and others recently showed that the activation of this ancestral specifically and rapidly stimulated (SI Results; Fig. S1; Movies S5, polarizing enzyme at the IS is required for MTOC polarization in + S6, S7, and S8). Taken together, the above results indicate that, in CD4 helper T cells interacting with dendritic cells (14, 15).
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