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Cross-Priming T Cell + Cell Licensing and CD8 Antigen Persistence Is Antigen Persistence Is Required for Dendritic Cell Licensing and CD8 + T Cell Cross-Priming This information is current as Hélène Jusforgues-Saklani, Martin Uhl, Nathalie Blachère, of September 26, 2021. Fabrice Lemaître, Olivier Lantz, Philippe Bousso, Deborah Braun, James J. Moon and Matthew L. Albert J Immunol 2008; 181:3067-3076; ; doi: 10.4049/jimmunol.181.5.3067 http://www.jimmunol.org/content/181/5/3067 Downloaded from References This article cites 40 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/181/5/3067.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antigen Persistence Is Required for Dendritic Cell Licensing and CD8؉ T Cell Cross-Priming1 He´le`ne Jusforgues-Saklani,*‡ Martin Uhl,*‡ Nathalie Blache`re,* Fabrice Lemaître,* Olivier Lantz,† Philippe Bousso,* Deborah Braun,*‡ James J. Moon,§ and Matthew L. Albert2*‡ It has been demonstrated that CD4؉ T cells require Ag persistence to achieve effective priming, whereas CD8؉ T cells are on “autopilot” after only a brief exposure. This finding presents a disturbing conundrum as it does not account for situations in which CD8؉ T cells require CD4؉ T cell help. We used a physiologic in vivo model to study the requirement of Ag persistence for the cross-priming of minor histocompatibility Ag-specific CD8؉ T cells. We report inefficient cross-priming in situations in which male -cells are rapidly cleared. Strikingly, the failure to achieve robust CD8؉ T cell activation is not due to a problem with cross presentation. In fact, by providing “extra help” in the form of dendritic cells (DCs) loaded with MHC class II peptide, it was Downloaded from possible to achieve robust activation of CD8؉ T cells. Our data suggest that the “licensing” of cross-presenting DCs does not occur during their initial encounter with CD4؉ T cells, thus accounting for the requirement for Ag persistence and suggesting that DCs make multiple interactions with CD8؉ T cells during the priming phase. These findings imply that long-lived Ag is critical for :efficient vaccination protocols in which the CD8؉ T cell response is helper-dependent. The Journal of Immunology, 2008, 181 3067–3076. http://www.jimmunol.org/ oth in vitro and in vivo experimentation have defined an It has also been demonstrated that CD8ϩ T cell priming may essential role for Ag-specific CD4ϩ helper cells in the occur following a relatively short exposure to Ag. In infection B cross-priming of CD8ϩ T cells (1–3). This helper activity situations such as Listeria monocytogenes, effective primary CD8ϩ requires that the Ag be present on the same APC that is engaging T cell responses require less than 24 h of antigenic stimulation (7, ϩ the CD8 T cell, much like the carrier effect that had been previ- 8). Similarly, it has been demonstrated in vitro, using monoclonal ously defined for T cell/B cell cooperation (4). This led to the T cells that CD8ϩ T cells given 20 h of stimulus will respond by proposal of three-cell clusters of T cells with APCs, as it could best proliferating extensively and differentiating into effector cells (8, explain the epitope linkage and noncognate requirements of the in 9). This phenomenon was termed an “autopilot” response by by guest on September 26, 2021 vivo cytolytic response. Due to an awareness that the probability Bevan and Fink (10), and distinguishes CD8ϩ T cell activation of such interactions would be rare as a result of the low pre- from the regulation of CD4ϩ T cell priming (11–13). Indeed, re- cursor frequency of naive T cells and the scarcity of Ag-loaded cent experiments from Obst et al. (14) demonstrated that CD4ϩ T APCs, this model gave way to what is commonly referred to as cell proliferation requires cognate stimulation throughout their ex- ϩ the “serial two-cell” model. Accordingly, CD4 T cells “li- pansion phase. These results raise a paradox regarding the priming 3 ϩ cense” dendritic cells (DCs) that in turn prime CD8 T cells. of helper-dependent CD8ϩ T cell responses: what happens if the This terminology was first introduced by Lanzavecchia (5), fol- DC makes contact with an Ag-specific CD8ϩ T cell before it is ϩ lowing from three studies that support the role of CD4 T cells “licensed?” The current model suggests that it would be tolerized, offering activation signals to the APC that permit them to prime even though the cognate helper cell may be present in the reper- ϩ CD8 T cells (2, 3, 6). toire, albeit late in getting to the Ag-loaded DCs. Moreover, the concept that DCs are licensed by CD4ϩ T cells during their initial encounter does not account for the need to first prime the CD4ϩ T *Immunology Department, Institut Pasteur, †Institut Curie, ‡Institut National de la cell and induce surface expression of CD40L, a critical molecule Sante´ et de la Recherche Me´dicale Unite´ 818, Paris France; and §Department of for DC activation. Immunology, University of Minnesota, MN 55455 To evaluate the requirement for Ag persistence during helper- Received for publication April 7, 2008. Accepted for publication June 25, 2008. dependent cross-priming and address the timing of DC licensing, The costs of publication of this article were defrayed in part by the payment of page we studied responses in female mice to the male Ag HY uty pep- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tide, which has the minor histocompatibility locus of Y chromo- 1 some in ubiquitously transcribed tetratricopeptide repeat gene uty. This work was supported in part by grants from Mildred Scheel Stipendium Deut- ϩ sche Krebshilfe e.V. (to M.U.), La Ligue Nationale Contre le Cancer, L’Agence´ In this model, CD8 T cells that recognize the uty peptide pre- Nationale de la Re´cherche, and The European Young Investigator Awards Scheme, sented by H-2Db are dependent on CD4ϩ T cell help during the European Science Foundation (to M.L.A.). priming phase (6, 15). Moreover, cross-priming to this epitope has 2 Address correspondence and reprint requests to Dr. Matthew L. Albert, Institut k3 b Pasteur, 25 rue du Dr. ROUX, Paris 75724, France. E-mail address: albertm@ been reported to be inefficient in models when allo (H2 H2 )or ␤ ␤ Ϫ/Ϫ pasteur.fr 2-microglobulin-deficient ( 2m ) cells are used as the source 3 Abbreviations used in this paper: DC, dendritic cell; CFDA-SE, carboxyfluorescein of male Ag (16, 17). Finally, the HY model is physiologically and ␤ ␤ diacetate succinimidyl ester; 2m, 2-microglobulin; DLN, draining lymph node; pathologically relevant because the minor histocompatibility Ags SFC, spot forming cell; WT, wild type. are normal cellular proteins and have been implicated in the clin- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 ical complications associated with graft-versus-host disease. We www.jimmunol.org 3068 Ag PERSISTENCE IS REQUIRED FOR CROSS-PRIMING FIGURE 1. Efficient cross-presentation of ␤ Ϫ/Ϫ 2m male cells does not permit effective cross-priming of H-2Db uty-specific CD8ϩ T cells. A, Female mice were immunized in- tradermally with 5 ϫ 106 CD11c-depleted splenocytes that had been isolated from WT ␤ Ϫ/Ϫ or 2m male mice. Live, nonclumped, lineage-positive cells were gated. Depletion was confirmed using FACS analysis. B, Af- ter 12 days, the efficiency of priming uty- specific CD8ϩ T cells was determined using IFN-␥ ELISPOT. Purified CD8ϩ T cells were restimulated ex vivo for 24 h using fe- male DCs loaded with uty peptide (F). Un- pulsed DCs served as a negative control (E). Downloaded from Each mouse is represented and the number of SFC per 106 total CD8ϩ T cells is mea- sured. Horizontal bars indicate the mean. This experiment is representative of eight similar experiments. C, To monitor cross- presentation of injected male Ag, the trigger- ϩ ing of MataHari CD8 T cell division was http://www.jimmunol.org/ assessed. A total of 2 ϫ 105 CFDA-SE- labeled MataHari CD8ϩ T cells (CD45.2) was transferred into recipient female mice (CD45.1), and T cell division was followed ␤ Ϫ/Ϫ 3 days after immunization with 2m male cells by gating on CD8␤ϩCD45.2ϩ cells. Results are representative of four in- dependent experiments from which 3/3 mice tested (1, 2, 3) are in one such experiment. by guest on September 26, 2021 ϩ report that contrary to the autopilot expansion of CD8 T cells that peptide dby (DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked) is used has been demonstrated in helper-independent models of CD8ϩ T in priming experiments. Labeling with carboxyfluorescein diacetate succin- cell priming, the priming of HY-reactive CD8ϩ T cells requires the imidyl ester (CFDA-SE) was performed using the Vybrant CFDA-SE cell tracer kit from Molecular Probes.
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