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The Journal of Immunology, 2006, 177: 1406-1410.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Cognate CD4 Help Promotes Recruitment of Antigen-Specific CD8 T Cells around Dendritic Cells1

Hélène Beuneu, Zacarias Garcia and Philippe Bousso2

G5 Dynamiques des Reponses Immunes, Equipe Avenir Inserm U668, Institut Pasteur, Paris, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
 References
 
The cellular orchestration underlying help provided by CD4 T lymphocytes to CD8 T cell responses is not fully understood. We documented that the formation of three-cell clusters occurred as soon as day 1 and relied on long-lasting CD4 and CD8 T cell interactions with dendritic cells (DCs). The influence of CD4 help on CD8 T cell differentiation could be observed as early as the second round of cell division. Importantly, our results identify a new facet to the phenomenon of CD4 help in which DCs, upon cognate interactions with CD4 T cells, increase their ability to attract/retain Ag-specific CD8 T cells. Our results support a model in which CD4 help operates rapidly, in part by favoring CD8 T cells recruitment around those DCs that are the most competent for priming.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
 References
 
In many instances, CD4 helper T cells promote the quality of CD8 T cell responses (reviewed in Ref. 1, 2). How CD4 T lymphocytes communicate with other cells during this process continues to be the subject of intense investigation. The initial model postulated that, by bringing together Ag-specific CD4 T cells and CD8 T cells, APCs served as a platform for CD8 T lymphocytes to benefit from IL-2 produced by neighboring CD4 T cells (3, 4). More recently, Bourgeois et al. (5) suggested that CD8 T cells directly interact with activated CD4 T cells via CD40-CD154 molecules. There is also ample evidence that CD4 T cells can act primarily on dendritic cells (DCs)3to increase their ability to stimulate CD8 T cells (6, 7, 8, 9). Interactions between CD40 and CD154 molecules expressed by DCs and activated CD4 T cells respectively can increase DC levels of costimulation molecules (10, 11, 12) and promote their ability to produce IL-12 (13, 14). Another intriguing question concerns the timing at which CD4 T cell help operates. A role of CD4 T cell help in programming the differentiation of naive CD8 T cells have been proposed (15). Alternatively, CD4 T cells could act at later time points, to maintain the number and function of CD8 memory T cells (16).

In this study, we show that CD4 help influences the early phases of CD8 T cell activation, in part by favoring interactions between CD8 T lymphocytes and DCs that are capable of cognate interactions with CD4 helper T cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Conclusion
 Disclosures
 References
 
Mice

C57BL/6 (B6) mice were purchased from Charles River Laboratories. Female Marylin TCR transgenic RAG-2–/– mice and CD40-deficient mice were obtained from the Centre de Distribution Typage et Archivage animal. OT-I TCR transgenic mice and mice expressing the GFP under the chicken beta-actin promoter were bred in our animal facility. All animal experiments were performed in accordance with the institutional guidelines for animal care.

Cell preparation and transfer

Splenic DCs were purified as described (17) and pulsed with the indicated concentration of S8L (SIINFEKL) and/or with 1 µM N15S (NAGFNSNRANSSRSS) peptide (NeoMPS) for 1 h at RT. CD4 T cells were collected from LNs of Marylin TCR RAG-2–/– mice. OT-I CD8 T cells were purified using the CD8 T cell isolation kit (Miltenyi Biotec). Cells were labeled with the indicated concentration of SNARF and/or CFSE dyes (Invitrogen Life Technologies).

FACS analysis

Lymph nodes (LN) were harvested and incubated at 37°C for 15 min in RPMI 1640 containing 1 mg/ml collagenase. Cells were stained with a combination of the following Abs: allophycocyanin-labeled anti-CD8, PE-labeled anti-CD25, anti-IFN-{gamma} (BD Biosciences), allophycocyanin-labeled anti-CD11c, PE-labeled anti-I-Ab, PE-labeled anti-Kb, PE-labeled anti-CD80, and PE-labeled anti-CD86 (BioLegend) mAbs. Intracellular IFN-{gamma} staining of LN cells was performed after a 4-h restimulation in the presence of 1 µM S8L peptide and 1 µg/ml brefeldin A.

Confocal and two-photon microscopy

LNs sections were analyzed by confocal microscopy as described (18). Two-photon imaging was performed using an upright Axioscope 2 FS microscope (Zeiss) and a Ti/sapphire laser (Coherent) tuned at 780 nm as described (18). Popliteal LNs were maintained at 37°C and superfused with medium bubbled with 95% O2 and 5% CO2. Images were acquired at >100 µm below the LN surface every 15 s.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Conclusion
 Disclosures
 References
 
Visualizing DCs interacting with Ag-specific CD4 and CD8 T cells in intact LNs

To gain some insight into the cellular orchestration underlying CD4 T cell help, we visualized interactions between Ag-bearing DCs and CD4 and CD8 T lymphocytes. DCs pulsed with the S8L peptide (recognized by the OT-I TCR) and the N15S peptide (recognized by the Marylin TCR) were labeled with vital dyes and injected in the footpad of recipient mice. Subsequently, dye-labeled OT-I CD8 T cells and Marylin CD4 T cells were injected iv. After 20 h, popliteal LNs were subjected to real-time two-photon imaging. Both Marylin CD4 T cells and OT-I CD8 T cells were found to establish interactions with DCs, and the majority of clusters (71%) contained the three cell types (DCs and CD4 and CD8 T cells). Most CD4 T cell–DC contacts (80%) as well as CD8 T cell–DC contacts (87%) were maintained during imaging periods of 20 min (Fig. 1, b and c; and Movies 1 and 2),4 indicating that these interactions were in the range of hours. Time-lapse movies suggested that CD8 T cells were generally retained within clusters through contact with DCs rather than through interactions with CD4 T cells (Fig. 1, b and c; and Movies 1 and 2). Our results suggest that information exchange between DCs and CD4 and CD8 T cells can occur in the early phases (<1 day) of the immune response prompting us to evaluate the role of CD4 T cell help on the initial stages of CD8 T cell activation.


Figure 1
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  		FIGURE 1. Three-cell clusters occur as stable CD4 and CD8 T cell interactions with DCs. DCs (3 x 106) were pulsed with S8L (0.1 µM) and N15S (1 µM) peptides, labeled with a mixture of SNARF (5 µM) and CFSE (2.5 µM), and injected in the footpad. Marilyn CD4 T cells (10 x 106) labeled with SNARF (10 µM) and OT-I CD8 T cells (20 x 106) labeled with CFSE (10 µM) were injected i.v. Popliteal LNs were subjected to two-photon imaging at 20 h. a, Most (17 of 24) clusters around DCs (yellow) contained both Ag-specific CD8 T cells (green) and CD4 T cells (red). b, Time-frame images showing that CD4 and CD8 T cells established long-lasting interactions with DCs. Time is indicated as minutes/seconds. Right panels depict trajectories of CD8 T cells (green), Ag-bearing DCs (yellow), and CD4 T cells (red). Two examples of clusters containing DCs and CD4 and CD8 T cells are shown together with one example of cluster containing DCs and CD8 T cells only. Stable interactions were observed whether or not CD4 T cells were present in the cluster. Scale bar, 10 µm. c, Graph shows the percentage of CD4 T cell–DC interactions (n = 15) and CD8 T–DC interactions (n = 47) maintained at the indicated time points.

 
Early imprinting of CD4 T cell help on CD8 T cell differentiation

We established an in vivo model to study the impact of CD4 help on CD8 T cell responses. Mice were transferred with Marylin CD4 T cells and immunized with DCs pulsed with S8L peptide (referred to as DCS8L) or with DCs pulsed with both S8L and N15S peptides (DCS8L+N15S). After 16 h, CFSE-labeled OT-I T cells were transferred in recipients (Fig. 2a). In this system, DCS8L and DCS8L+N15S can stimulate OT-I CD8 T cells, but cognate CD4 help could only be delivered during immunization with DCS8L+N15S. Proliferation and expression of CD25 were assessed as several studies have linked sustained CD25 expression with efficient T cell activation (19, 20, 21). Although immunization with DCS8L and DCS8L+N15S induce a similar level of OT-I T cell proliferation, DCS8L+N15S, but not DCS8L, promoted expression of the CD25 molecule (Fig. 2, b and c). In addition, OT-I T cells stimulated by DCS8L+N15S were approximately two times more likely to produce IFN-{gamma} at 48 h than OT-I T cells stimulated by DCS8L (Fig. 2, d and e) and produced more of this cytokine on a per-cell basis (mean fluorescence intensity (MFI) 2153 ± 81 vs 817 ± 34, respectively). These results support the idea that CD4 T cells rapidly instruct the differentiation of naive CD8 T cells.


Figure 2
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  		FIGURE 2. Cognate CD4 help impacts on the early stages of CD8 T cell activation. a, DCs (1.5 x 106) were pulsed with 0.1 nM S8L peptide alone (DCS8L) or in conjunction with 1 µM N15S peptide (DCS8L+N15S) and were injected in the footpad. Recipients were adoptively transferred with Marilyn CD4 T cells (2 x 106), and 16 h later, with CFSE-labeled OT-I CD8 T cells (3 x 106). b, DCS8L+N15S, but not DCS8L, promote CD25 expression on OT-I CD8 T cells. Numbers indicate the percentage of divided cells falling into the indicated region. c, The percentage of CD25+ OT-I CD8 T cells is graphed as a function of the number of cell division. d and e, OT-I CD8 T cells were assayed for IFN-{gamma} production by intracellular staining. f, MFI of IFN-{gamma}-producing OT-I CD8 T cells in the presence or absence of cognate CD4 help. Results are representative of four independent experiments.

 
Role of DC maturation during CD4 T cell help

Next, we assessed whether helper T cells were enhancing the quality of the CD8 T cell response by increasing expression of CD80/CD86 costimulation molecules on DCs. We examined the phenotype of GFP-expressing DCs that migrated to the LN following footpad injection, in the presence or absence of cognate interactions with CD4 T cells. As previously reported (17), DCs that had migrated to the draining LN displayed a mature phenotype with high level of MHC class II and CD80 and CD86 molecules (Fig. 3). Interestingly, cognate interactions with CD4 T cells did not result in additional changes in the level of expression of these markers (Fig. 3). Thus, in our system, CD4 help did not translate into increased CD80/CD86 costimulation molecules on DCs. Based on our results and those from other studies (22, 23), we conclude that, in some experimental systems, signals provided by CD4 help and those responsible for DC maturation are at least partly distinct.


Figure 3
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  		FIGURE 3. Cognate CD4 help does not alter expression of maturation markers on DCs. DCS8L or DCS8L+N15S were injected in the footpad of recipient mice and Marylin CD4 T cells (2 x 106) were injected iv. After 20 h, GFP-expressing DCS8L or DCS8L+N15S recovered from the popliteal LN were analyzed by flow cytometry, as were DCs before injection. a, Expression of MHC class II (I-Ab), MHC class I (Kb), CD80 and CD86 molecules at the surface of DCS8L+N15S (bold lines), or DCS8L (thin lines). b, MFI for the different markers is graphed for DCS8L or DCS8L+N15S. These results are representative of three independent experiments.

 
Preferential recruitment of CD8 T cells by DCs that engage in cognate interactions with Ag-specific CD4 T cells

Although previous studies have indicated that cognate helper T cells are not required for the formation of stable CD8 T cell–DC contacts (17, 24, 25), it was still possible that CD8 T cell–DC interactions were influenced by the presence of CD4 help. To test this possibility, we compared the clustering of CD8 T cells around DCs that were capable or incapable of establishing interactions with cognate CD4 T cells. Dye-labeled DCS8L+N15S and DCS8L were mixed and injected in female B6 mice (Fig. 4a). Recipients were then adoptively transferred with unlabeled Marylin CD4 T cells and after 16 h, with dye-labeled OT-I CD8 T cells. After 3h, LNs were sectioned and analyzed by confocal microscopy (Fig. 4b). Clustering of CD8 T cells around DCs was quantified using two different methods (Fig. 4c). First, we counted for each DC the number of OT-I T cells for which a zone of interaction with the DC was detected (contact method). We also quantified cell clustering by counting the number of OT-I T cells included within a 30-µm diameter circle centered around each DC (circle method), a more sensitive method that can however occasionally include OT-I T cells that were not truly in contact with the DC. For each image, we recorded and plotted the mean number of OT-I T cells clustered around each DCS8L against the number of OT-I T cells clustered around each DCS8L+N15S. We repeatedly found that DCS8L+N15S recruited significantly more OT-I T cells than DCS8L in a 3-h period (p < 0.01, Wilcoxon paired test). In the same image, there were on average 1.4–2.2 (depending on the quantitation method and the experiment) more CD8 T cells around DCS8L+N15S than around DCS8L (Fig. 4d, left and center panels, and Table I). As a control, CD8 T cell recruitment was virtually equivalent between two populations of dye-labeled DCS8L (Table I). The difference in recruitment was also observed when we averaged clustering values for each individual DCs (Fig. 4d, right panel) compiled from the different images of the same lymph node. In addition, DCS8L+N15S were again more competent than DCS8L to recruit CD8 T cells when clusters were analyzed at 24 h after CD8 T cell transfer or when we used a lower concentration of S8L peptide (0.1 nM instead of 10 nM) to pulse DCs (data not shown). Altogether, these results suggest that following interactions with CD4 T cells, DCs increase their ability to recruit CD8 T cells. The difference in clustering around DCS8L+N15S and DCS8L illustrates the importance for CD4 and CD8 T cells to recognize Ag on the same APCs.


Figure 4
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  		FIGURE 4. Cognate CD4 help promotes recruitment of Ag-specific CD8 T cells around DCs. a, DCS8L and DCS8L+N15S were labeled with SNARF or CFSE, respectively, mixed and injected in the footpad. Unlabeled Marilyn CD4 T cells (5 x 106) were injected i.v., and 16 h later, OT-I CD8 T cells (10 x 106) labeled with a mixture of SNARF and CFSE dyes were injected i.v. Popliteal LNs were collected after 3 h, sectioned, and processed for confocal microscopy. b, Clustering of OT-I CD8 T cells (yellow) around DCS8L (red) and DCS8L+N15S (green). Scale bar, 10 µm. c, Two different methods were used to quantify interactions (see text for details). d, For each image, the mean number of CD8 T cells clustered around DCS8L is plotted against the same value for DCS8L+N15S using the contact (left panel) or the circle method (center panel). Each dot represents an image containing an average of eight DCs. DCS8L+N15S were more efficient than DCS8L in recruiting OT-I T cells. Right panel displays the cluster size for each DCS8L and DCS8L+N15S analyzed (circle method). Average values were 3.5 ± 0.3 (mean + SEM) CD8 T cells for DCS8L vs 4.8 ± 0.3 CD8 T cells for DCS8L+N15S. e, Regulation of CD8 T cell recruitment by cognate CD4 help implicates CD40 expression on DCs. CD8 T cells clustered around WT DCS8L+N15S is plotted against the same value for CD40–/– DCS8L+N15S. Right panel shows the cluster size around each WT or CD40–/– DCS8L+N15S (circle method). Average values were 2.5 ± 0.2 and 3.5 ± 0.3 CD8 T cells around CD40–/– DCS8L+N15S and WT DCS8L+N15S. Scale bar, 10 µm; *, p < 0.003; **, p < 0.04, (Mann-Whitney U test).

 

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  		Table I. Cognate CD4 help promotes CD8 T cell–DC interactionsa

 
To assess whether CD40 expression on DCs was implicated in the observed regulation of CD8 T cells recruitment, we compared the clustering of OT-I T cells around DCS8L+N15S prepared from wild-type (WT) and CD40–/– mice. As shown in Fig. 4e, WT DCS8L+N15S recruited significantly more OT-I T cells than CD40–/– DCS8L+N15S in a 3-h period (p < 0.01, Wilcoxon paired test). In the same image, there were on average 1.5 (respectively 1.8) more CD8 T cells around WT DCs than around CD40–/– DCs using the contact method (respectively, circle method) of cluster quantification. This result strongly suggests that the DCs ability to recruit CD8 T cells is regulated by engagement of CD40 molecule expressed by DCs.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
Disclosures
 References
 
Three important conclusions can be drawn from the present study. First, CD4 help can impact on CD8 T cell differentiation very rapidly resulting in sustained CD25 expression and improved ability to produce IFN-{gamma}. Second, three-cell clusters form as early as day 1 and rely on long-lasting CD4 and CD8 T cell contacts with DCs. Third, CD4 help increases the ability of DCs to recruit CD8 T cells, likely reflecting an enhanced ability of DCs engaging helper CD4 T cells to attract and/or retain CD8 T cells. In this respect, it will be interesting to investigate the role of chemokines and/or adhesion molecules. This phenomenon likely reflects that CD4 help promotes a net gain of stimulation for CD8 T cells by favoring T cell arrest on DC (25), and/or by increasing the duration of CD8 T cell–DC contacts. Interestingly, the preferential association between CD8 T cells and DCs establishing cognate interaction with helper T cells also increases the opportunity for CD8 T cells to benefit from IL-12 produced by licensed DCs (13, 14, 26), or from IL-2 produced by neighboring CD4 T lymphocytes. We propose that, by controlling the duration and the location of CD8 T cell engagement on DCs, helper T cells optimize the set of signals received by CD8 T lymphocytes.


   Acknowledgments
 
We thank the Plate-forme d’Imagerie Dynamique, Institut Pasteur, and J. Di Santo, M. Albert, and E. Robey for helpful comments on the manuscript.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This study was supported by Pasteur Institute, Institut National de la Santé et de la Recherche Médicale, Agence Nationale de la Recherche, Association pour la Recherche contre le Cancer, Mairie de Paris, Fondation de France, and Network of Excellence MUGEN Grant FP6 005203 from the European Community. Back

2 Address correspondence and reprint requests to Dr. Philippe Bousso, G5 Dynamiques des Réponses Immunes, Equipe Avenir, Institut National de la Santé et de la Recherche Médicale U668, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris Cedex 15, France. E-mail address: bousso{at}pasteur.fr Back

3 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; WT, wild type; MFI, mean fluorescence intensity. Back

Received for publication March 20, 2006. Accepted for publication May 30, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusion
 Disclosures
 References
 

  1. Bevan, M. J.. 2004. Helping the CD8+ T-cell response. Nat. Rev. Immunol. 4: 595-602. [Medline]
  2. Behrens, G., M. Li, C. M. Smith, G. T. Belz, J. Mintern, F. R. Carbone, W. R. Heath. 2004. Helper T cells, dendritic cells and CTL Immunity. Immunol. Cell Biol. 82: 84-90. [Medline]
  3. Keene, J. A., J. Forman. 1982. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155: 768-782. [Abstract/Free Full Text]
  4. Cassell, D., J. Forman. 1988. Linked recognition of helper and cytotoxic antigenic determinants for the generation of cytotoxic T lymphocytes. Ann. NY Acad. Sci. 532: 51-60. [Abstract]
  5. Bourgeois, C., B. Rocha, C. Tanchot. 2002. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297: 2060-2063. [Abstract/Free Full Text]
  6. Ridge, J. P., F. Di Rosa, P. Matzinger. 1998. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393: 474-478. [Medline]
  7. Schoenberger, S. P., R. E. Toes, E. I. van der Voort, R. Offringa, C. J. Melief. 1998. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393: 480-483. [Medline]
  8. Bennett, S. R., F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. Miller, W. R. Heath. 1998. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393: 478-480. [Medline]
  9. Smith, C. M., N. S. Wilson, J. Waithman, J. A. Villadangos, F. R. Carbone, W. R. Heath, G. T. Belz. 2004. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat. Immunol. 5: 1143-1148. [Medline]
  10. Caux, C., C. Massacrier, B. Vanbervliet, B. Dubois, C. Van Kooten, I. Durand, J. Banchereau. 1994. Activation of human dendritic cells through CD40 cross-linking. J. Exp. Med. 180: 1263-1272. [Abstract/Free Full Text]
  11. Yang, Y., J. M. Wilson. 1996. CD40 ligand-dependent T cell activation: requirement of B7-CD28 signaling through CD40. Science 273: 1862-1864. [Abstract/Free Full Text]
  12. Grewal, I. S., H. G. Foellmer, K. D. Grewal, J. Xu, F. Hardardottir, J. L. Baron, C. A. Janeway, Jr, R. A. Flavell. 1996. Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273: 1864-1867. [Abstract/Free Full Text]
  13. Cella, M., D. Scheidegger, K. Palmer-Lehmann, P. Lane, A. Lanzavecchia, G. Alber. 1996. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J. Exp. Med. 184: 747-752. [Abstract/Free Full Text]
  14. Koch, F., U. Stanzl, P. Jennewein, K. Janke, C. Heufler, E. Kampgen, N. Romani, G. Schuler. 1996. High level IL-12 production by murine dendritic cells: up-regulation via MHC class II and CD40 molecules and down-regulation by IL-4 and IL-10. J. Exp. Med. 184: 741-746. [Abstract/Free Full Text]
  15. Janssen, E. M., N. M. Droin, E. E. Lemmens, M. J. Pinkoski, S. J. Bensinger, B. D. Ehst, T. S. Griffith, D. R. Green, S. P. Schoenberger. 2005. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434: 88-93. [Medline]
  16. Sun, J. C., M. A. Williams, M. J. Bevan. 2004. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 5: 927-933. [Medline]
  17. Bousso, P., E. Robey. 2003. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat. Immunol. 4: 579-585. [Medline]
  18. Celli, S., Z. Garcia, P. Bousso. 2005. CD4 T cells integrate signals delivered during successive DC encounters in vivo. J. Exp. Med. 202: 1271-1278. [Abstract/Free Full Text]
  19. Gett, A. V., F. Sallusto, A. Lanzavecchia, J. Geginat. 2003. T cell fitness determined by signal strength. Nat. Immunol. 4: 355-360. [Medline]
  20. van Stipdonk, M. J., G. Hardenberg, M. S. Bijker, E. E. Lemmens, N. M. Droin, D. R. Green, S. P. Schoenberger. 2003. Dynamic programming of CD8+ T lymphocyte responses. Nat. Immunol. 4: 361-365. [Medline]
  21. Itano, A. A., S. J. McSorley, R. L. Reinhardt, B. D. Ehst, E. Ingulli, A. Y. Rudensky, M. K. Jenkins. 2003. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19: 47-57. [Medline]
  22. Albert, M. L., M. Jegathesan, R. B. Darnell. 2001. Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells. Nat. Immunol. 2: 1010-1017. [Medline]
  23. Fujii, S., K. Liu, C. Smith, A. J. Bonito, R. M. Steinman. 2004. The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J. Exp. Med. 199: 1607-1618. [Abstract/Free Full Text]
  24. Mempel, T. R., S. E. Henrickson, U. H. Von Andrian. 2004. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427: 154-159. [Medline]
  25. Hugues, S., L. Fetler, L. Bonifaz, J. Helft, F. Amblard, S. Amigorena. 2004. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nat. Immunol. 5: 1235-1242. [Medline]
  26. Curtsinger, J. M., D. C. Lins, M. F. Mescher. 2003. Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector function. J. Exp. Med. 197: 1141-1151. [Abstract/Free Full Text]



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