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The Journal of Immunology, 2004, 173: 2217-2221.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Distinct Roles for T Help and CD40/CD40 Ligand in Regulating Differentiation of Proliferation-Competent Memory CD8+ T Cells1

Martin F. Bachmann2,*, Katrin Schwarz*, Petra Wolint{dagger}, Edwin Meijerink*, Stephen Martin*, Vania Manolova* and Annette Oxenius2,{dagger}

* Cytos Biotechnology AG, Zurich-Schlieren, Switzerland; and {dagger} Swiss Federal Institute of Technology, Institute for Microbiology, Zurich, Switzerland


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Murine primary antiviral cytotoxic T cell (CTL) responses are often induced in the absence of Th cells. In this study, we show that virus-like particles, if combined with DNA rich in CpG motifs, efficiently trigger primary CTL responses and comparable frequencies of memory CTLs in the presence or absence of T help. However, memory CTLs primed in the absence of T help failed to proliferate upon viral challenge. Nevertheless, they were efficiently recruited to sites of inflammation, indicating that T help may regulate the balance between proliferation-competent and migration-competent memory CTLs. Surprisingly, generation of proliferation-competent memory CTLs was completely independent of CD40 or CD40L, molecules commonly assumed to be central for mediating the beneficial effects of Th cells on CTL development. Thus, Th cells but not CD40/CD40L are key for the differentiation of proliferation-competent central memory CD8+ T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Induction and maintenance of T cell memory is a field of major interest and controversy. The various definitions of "T cell memory" are in part responsible for the discrepancy in results and particularly in their interpretations. Most textbooks define immunological memory as the ability to mediate faster and stronger secondary immune responses. Increased frequencies of specific T cells lead to such accelerated T cell responses and are therefore considered by some to be the most important aspect of T cell memory. In contrast, memory T cells can mediate protection from reinfection, which is the litmus test for T cell memory for other investigators (for reviews, see Refs.1, 2, 3, 4). More recently, T cell memory has also been interpreted as the ability of memory T cells to rapidly proliferate and expand as a population upon re-exposure to Ag (5, 6, 7, 8). This latter way to look at T cell memory has the advantage that it takes into account both the presence of increased precursor frequencies and their ability to quickly expand, a combination that may correlate with an enhanced ability to protect from reinfection. Nevertheless, because memory T cells may be categorized into more resting, proliferation-competent "central memory T cells," and more activated, proliferation-incompetent but homing-competent "effector memory T cells," assessment of T cell proliferation as a readout for T cell memory may predominantly identify central memory T cells (9, 10, 11).

In the present study, we assessed the role of Th cells and of CD40/CD40L in the priming of CD8+ T cells and in the generation of proliferation- vs homing-competent memory CTLs. As a model Ag, we used the lymphocytic choriomeningitis virus (LCMV)3 glycoprotein-derived peptide gp33, displayed on virus-like particles (VLPs) derived from the bacteriophage Q{beta} (12). We deliberately chose a replication-incompetent and short-lived Ag to avoid prolonged Ag persistence or low-level virus replication as additional factors influencing the quantity and quality of memory CTL development.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice and viruses and VLPs

C57BL/6, Smarta TCR transgenic, CD40–/–, CD40L–/–, MHC class II–/–, and RAG2–/– mice were maintained in a specific pathogen-free facility and mice were immunized between 8 and 12 wk of age. Animal experiments were performed according to the regulations of the cantonal veterinary office.

Recombinant vaccinia virus expressing LCMV glycoprotein (VVG2) was originally obtained from Dr. D. Bishop (Oxford University, Oxford, U.K.) and grown on BSC cells at low multiplicity of infection, and quantification was performed as described (12).

gp33-VLPs based on peptide gp33 coupled to VLPs derived from the bacteriophage Q{beta} have been described previously (13). Packaging of CpG oligonucleotides (5'-GGGGTCAACGTTGAGGGGGG-3', thioester stabilized) into the gp33-VLPs was performed as described previously (13). Mice were immunized with 100 µg of gp33-VLPs. gp33-gp61-VLPs were produced analogously and contained the peptide CKSLKAVYNFATMGLNGPDIYKGVYQFKSVEF.

CpG-loaded VLPs or native (unloaded) VLPs were labeled with Alexa 488 by using the Alexa Fluor 488 Labeling kit (Molecular Probes, Leiden, The Netherlands) according to manufacturer’s protocol.

Viral challenge

Vaccinated female mice were infected i.p. with 2 x 106 PFU VVG2. Seven days later, ovaries were collected, and the vaccinia titers were determined by plaque assay on BSC 40 cells as described (12).

Abs and peptide MHC class I tetramers

Allophycocyanin- or PE-conjugated peptide/MHC class I tetrameric complexes were generated as previously described (14). The following anti-mouse mAbs and allophycocyanin-conjugated streptavidin were purchased from BD Pharmingen (Allschwil, Switzerland): anti-CD107a (FITC), anti-IFN-{gamma} (FITC or PE or allophycocyanin), anti-CD8 (PerCP), and anti-CD62L (allophycocyanin).

Immunofluorescent staining and analysis

For direct staining, whole-blood or single-cell suspensions from spleens or ovaries were used. Cells were incubated for 20 min at 4°C with peptide/MHC tetramers together with anti-CD8 and anti-CD62L-specific Abs. For intracellular IFN-{gamma} staining and for analysis of Ag-induced degranulation, cells were stimulated with gp33 peptide in the presence of anti-CD107a Ab for 6 h, washed, surface stained at 4°C, fixed/permeabilized, stained intracellularly, and analyzed by four-color flow cytometry (FACSCalibur; BD Biosciences, Basel, Switzerland).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Th cell-dependent vs -independent primary CTL responses: activation of the APCs makes the difference

Peptide gp33 derived from LCMV glycoprotein is the dominant CTL epitope in C57BL/6 mice. We have previously shown that peptide gp33 fused to VLPs derived from hepatitis B core Ag induces strong CTL responses if given together with innate stimuli, such as DNA oligonucleotides rich in CpG motifs (CpGs) (12). Induction of CTL responses was particularly efficient if CpGs were not simply mixed with but packaged within the VLPs (13). These results were confirmed in this study, because peptide gp33 chemically coupled to Q{beta} (gp33-VLP) induced ~2-fold weaker CTL responses compared with VLPs whose naturally packaged RNA was replaced by CpGs (gp33-VLP/CpG) (Fig. 1A). The influence of CD40 and T help on the induction of CTL responses was assessed next, because it has been shown previously that CD8+ T cell responses to protein Ags can be induced in the absence of CD4+ T cells or CD40/CD40L interaction (15, 16). To this end, CD40- and MHC class II-deficient mice were immunized with gp33-VLPs or gp33-VLPs/CpGs, and frequencies of specific T cells were assessed 8 days later. CD40-deficient and MHC class II-deficient mice, lacking Th cells, mounted normal CTL responses upon vaccination with gp33-VLPs/CpGs. In addition, unhelped CTLs appeared properly activated, because the majority of specific CD8+ T cells exhibited down-regulated levels of CD62L. In sharp contrast, MHC class II-deficient mice completely failed to mount a response against gp33-VLPs in the absence of CpGs, whereas CD40-deficient mice mounted CTL responses comparable to C57BL/6 mice. Thus, the requirement of Th cells for CTL priming upon gp33-VLP vaccination can be replaced by APC-activating CpGs. Furthermore, the beneficial effect of Th cells on CTL priming by gp33-VLPs was CD40 independent.



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  		FIGURE 1. A, gp33-specific CD8+ T cell expansion 8 days after VLP immunization. C57BL/6, CD40–/–, and MHC class II (MHCII)–/– mice were immunized s.c. with 100 µg of gp33-VLP/CpG (upper panels) or with 100 µg of gp33-VLP (lower panels). Eight days after immunization, gp33-specific CD8+ T cell frequencies (left panels) and the percentage of tetramer+CD8+ T cells expressing CD62L (right panels) were measured in the blood. Each circle represents a single mouse. B, VLP/CpGs induce maturation of DCs in vivo. Mice were immunized s.c. with 50 µg of Alexa 488-labeled VLP/CpGs, Alexa 488-labeled VLPs, or with 200 µl of PBS. Eighteen hours later, draining LN were isolated and single-cell suspensions were stained for the expression of CD11c and CD86. CD11c+Alexa+ (upper panel) and CD11c+Alexa– (lower panel) cells were analyzed for the expression of CD86. Mean fluorescence intensities for CD86 stainings are depicted as numbers in the respective plots. C, Evolution of LCMV gp33-specific CD8+ T cells frequencies 8–50 days after VLP immunization. C57BL/6, CD40–/–, and MHCII–/– mice were immunized s.c. with 100 µg of gp33-VLP/CpG, and gp33-specific CD8+ T cell frequencies (upper panels) and the percentage of tetramer+CD8+ T cells expressing CD62L (lower panels) were measured at the indicated time points (mean ± SD). One of three similar experiments is shown.

 
To directly assess whether VLP/CpGs induced maturation of dendritic cells (DCs) in vivo, we labeled the VLPs with the fluorochrome Alexa 488, allowing the identification of DCs that had taken up VLPs in vivo. Alexa 488-VLP/CpGs were injected s.c., and draining lymph nodes (LN) were isolated 18 h later. Single-cell suspensions were stained for the expression of CD11c and CD86. CD86 expression was clearly up-regulated on DCs that had taken up Alexa 488-VLP/CpGs if compared with DCs from the same animal that had not taken up Alexa 488-VLP/CpGs (mean fluorescence intensity of 763 vs 352; Fig. 1B). Similar results were obtained for DCs isolated from B6 or MHC class II-deficient mice (not shown). For comparison, mice were also injected with Alexa 488-VLPs that had not been loaded with CpGs. Uptake of Alexa-VLPs resulted in reduced but significant up-regulation of CD86 expression if compared with control DCs. Most likely, the VLP-induced maturation was triggered by the bacterial RNA naturally packaged into the VLPs, because ssRNA was recently shown to be a ligand for TLR7/8 (17, 18).

These data confirm that activation of DCs is critical for efficient priming of CTL responses in the absence of Th cells. Intermediate activation of DCs by gp33-VLPs (Fig. 1B) was not sufficient to drive primary CTL responses in the absence of T help, indicating that different TLR ligands (ssRNA vs CpGs) may differ in their potency to drive CTL responses (19).

Similar frequencies of memory CTLs develop in the presence or absence of CD40 and Th cells

Next, we measured the development of memory T cells by longitudinal tetramer stainings. C57BL/6 mice, CD40–/–, and MHC class II–/– mice were immunized with gp33-VLP/CpG, and gp33-specific T cells were assessed at various time points after vaccination (Fig. 1C). CTL frequencies were maximal around day 8 after immunization and declined at similar rates in all mouse strains thereafter. Moreover, the proportion of CD62L-expressing gp33-specific CD8+ T cells was similar in the various mouse strains, indicating that frequencies and activation status of memory T cells were similar in the presence or absence of CD40 or T help.

Memory CTLs primed in the absence of T help fail to proliferate in vivo

The ability of memory CTLs to proliferate upon re-exposure to Ag was tested next. C57BL/6 mice as well as MHC class II–/– and CD40–/– mice were primed with gp33-VLP/CpGs or gp33-VLPs and challenged 50 or 43 days later with recombinant vaccinia virus expressing LCMV glycoprotein (VVG2). Frequencies of specific T cells dramatically increased in control and CD40–/– mice upon challenge with VVG2 (Fig. 2A). In addition, proliferating T cells rapidly lost expression of CD62L, indicating that the cells became effectors (data not shown). Thus, memory CTLs induced by vaccination with gp33-VLPs and gp33-VLP/CpG were proliferation competent even if they were generated in the absence of CD40-CD40L interaction. In contrast, memory T cells generated in complete absence of T help failed to proliferate upon re-exposure to Ag, irrespective of whether APC-activating CpGs were present or absent in the priming vaccine. Thus, as reported previously, unhelped memory CTLs are proliferation incompetent (5, 6, 7, 8). Interestingly, a significant proportion of the few unhelped memory CTLs present at the time of challenge down-regulated expression of CD62L, indicating that these cells could still show signs of activation but failed to proliferate (data not shown).



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  		FIGURE 2. Challenge of VLP-immunized mice with VVG2. A, C57BL/6, CD40–/–, and MHC class II (MHCII)–/– mice were immunized s.c. with 100 µg of gp33-VLP/CpG (left panels) or with 100 µg of gp33-VLP (right panels) and 50 or 43 days after immunization, mice were challenged by i.p. infection with 2 x 106 PFU of VVG2. Four and 7 days after challenge, gp33-specific CD8+ T cell frequencies were measured by tetramer staining in the blood (mean ± SD). B, Expansion of gp33-specific CD8+ T cells in spleen and LN after secondary challenge with VVG2. Mice were immunized with 100 µg of gp33-VLP/CpG, and 50 days later, frequencies of gp33-specific CD8+ T cells were determined before ("pre") and 7 days after ("post") VVG2 challenge in spleen and LN (mean ± SD). C, IFN-{gamma} production and CD44 expression of gp33-specific CD8+ T cells from the same mice as in B was assessed in the spleen before and 7 days after VVG2 challenge (mean ± SD). One of three similar experiments is shown.

 
Expansion of memory CTLs after VVG2 challenge was also observed at comparable levels in spleens of B6 and CD40–/– mice, whereas no significant expansion occurred in MHC class II–/– mice (Fig. 2B). Expansion of tetramer-stainable memory CTLs correlated with increased frequencies of IFN-{gamma}-producing gp33-specific CD8+ T cells after secondary challenge (Fig. 2C). gp33-specifc CD8+ T cells from B6, CD40–/–, and MHC class II–/– mice expressed high levels of CD44 before and after secondary challenge (Fig. 2C). Proliferation of memory CTLs was much less apparent in the mesenteric LN after challenge with VVG2 (Fig. 2B).

These data indicate that activation of DCs by CpGs during CTL priming is not sufficient for induction of proliferation-competent memory CTLs in the absence of T help. Thus, activation of DCs may be necessary and sufficient for the induction of acute CTL responses. In contrast, DC activation is necessary but not sufficient for the generation of proliferation-competent memory CTLs. CD40 was dispensable both for the induction of acute and the generation of memory CTL responses. Thus, Th cells facilitate generation of memory CTLs by mechanisms other than CD40-mediated activation of APCs, probably including the production of cytokines or alternative pathways of modulating APC function.

Unhelped memory CTLs are efficiently recruited to peripheral infected organs

Whether the different memory CTLs are able to home to infected target organs was assessed next. Female C57BL/6, CD40-, CD40L-, and MHC class II-deficient mice were immunized with gp33-VLP/CpG and challenged 55 days later with VVG2. Frequencies of specific T cells were determined 7 days later in ovaries (Fig. 3A), where massive viral replication is occurring (Fig. 3B), as well as in spleens and blood of challenged mice (where no viral replication is occurring, not shown). As expected, C57BL/6, CD40-, and CD40L-deficient mice had high frequencies of specific T cells in blood, spleen, as well as ovaries (Fig. 3, A and B). In contrast, MHC class II-deficient mice had low frequencies of specific T cells in blood and spleen. Surprisingly, frequencies of specific T cells were close to normal in infected ovaries. Thus, unhelped memory CTLs may fail to proliferate but are nevertheless efficiently recruited to infected target organs.



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  		FIGURE 3. Differential localization of gp33-specific CD8+ T cells in VLP-immunized and VVG2-challenged mice in blood, spleen, and ovaries. C57BL/6, CD40L–/–, CD40–/–, and MHC class II (MHCII)–/– mice were immunized s.c. with 100 µg of gp33-VLP/CpG, and 55 days later, mice were challenged by i.p. infection with 2 x 106 PFU of VVG2. Seven days after challenge, gp33-specific CD8+ T cell frequencies were measured by tetramer staining in blood, spleen, and ovaries. A, Representative example of tetramer staining in spleen and ovaries 7 days after VVG2 challenge. B, Frequencies of gp33-specific CD8+ T cells in blood, spleen, and ovaries; the mean ± SD of three to four mice per group is shown. In the right panel, vaccinia virus titers in ovaries from the same time point are shown. C, The ability of CD8+ T cells to respond to gp33 stimulation was assessed by their degranulation (i.e., their relocalization of the lytic granule membrane protein CD107 to the cell surface; left graph) or their IFN-{gamma} production (middle left graph). The percentage of gp33tet+CD8+ T cells able to degranulate is shown in the middle right graph, and the percentage of gp33tet+CD8+ T cells able to produce IFN-{gamma} is shown in the right graph. The mean ± SD of three to four mice per group and one of two similar experiments is shown.

 
The expanded gp33-specific CD8+ T cells in the spleens of VVG2-challenged B6, CD40L-, or CD40-deficient mice were analyzed for their ability to degranulate and to produce IFN-{gamma} upon peptide stimulation (Fig. 3C). Degranulation was assessed by Ag-induced cell surface expression of the lytic granule membrane marker CD107a (20). Expanded gp33-specific CD8+ T cells were equally able to degranulate and to produce IFN-{gamma} upon gp33 stimulation, demonstrating that the lack of CD40 or CD40L had no consequences for the functional qualities of gp33-specific CD8+ T cells. Furthermore, the low frequencies of gp33-specfic CD8+ T cells in the spleen of MHC class II–/– mice were also functional in terms of IFN-{gamma} production and degranulation because comparable fractions of gp33-tetramer-positive cells were able to produce IFN-{gamma} and to degranulate in B6, CD40-, CD40L-, and MHC class II-deficient mice (Fig. 3C).

To corroborate these findings in a different experimental setup, we adoptively transferred purified naive CD8+ T cells in RAG-deficient recipient mice with or without cotransfer of purified naive LCMV gp61-specific TCR transgenic CD4+ T cells. Recipient mice were immunized with gp33-gp61-VLP/CpG, and expansion of gp33-specific CD8+ T cells was monitored (Fig. 4A). In both recipient groups, gp33-specific CD8+ T cells had expanded 8 days after immunization, and frequencies had declined by day 29 after immunization. At day 29, recipient mice were challenged by VVG2 infection, and secondary expansions of gp33-specific CD8+ T cells were observed in blood and spleen of recipients that had received both CD8+ and CD4+ T cells; however, no significant expansion was observed in recipients that had received only CD8+ T cells (Fig. 4). In contrast, in the ovaries of challenged mice, there was no difference in the frequencies of gp33-specific CD8+ T cells between the two different groups of mice, indicating again that unhelped CTLs were not impaired in their migration to infected organs (Fig. 4B).



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  		FIGURE 4. Differential localization of gp33-specific CD8+ T cells in VLP-immunized and VVG2-challenged mice in blood, spleen, and ovaries. A total of 4 x 106 purified naive CD8+ T cells (95% purity) from C57BL/6 mice was transferred into RAG2-deficient mice with concomitant anti-CD4 depletion (injection of 200 µg of rat anti-mouse CD4 mAb YTS191 two times), or 4 x 106 purified naive CD8+ T cells from C57BL/6 mice were cotransferred with 6 x 106 purified naive CD4+ T cells from LCMV gp61-specific TCR transgenic mice (90% purity). Five hours later, recipient mice were challenged s.c. with 100 µg of gp33-gp61-VLP/CpG. A, Frequencies of gp33-specific CD8+ T cells in blood 8 and 29 days after immunization and 7 days after VVG2 challenge (mean ± SD). B, Frequencies of gp33-specific CD8+ T cells in spleen and ovaries 7 days after VVG2 challenge and frequencies of CD8+ T cells able to degranulate after gp33 stimulation in spleen 7 days after VVG2 challenge. The mean ± SD of three mice per group is shown. One of two similar experiments is shown.

 
Conclusion

The present study demonstrates that development of proliferation-competent memory CTLs occurs normally in the absence of CD40/CD40L interaction, whereas it is severely impaired in the absence of Th cells, despite normal primary CTL responses. However, unhelped CTLs were efficiently recruited to peripheral infected organs and differentiated normally into effector cells. These results suggest that T help regulates the balance between proliferation-competent vs homing-competent memory CTLs.


   Acknowledgments
 
We thank Petra Jäger for excellent technical assistance and Manfred Kopf for helpful discussions.


   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 work was supported by the Roche Research Fund for Biology, the Swiss National Science Foundation, and the Vontobel Foundation. Back

2 Address correspondence and reprint requests to Dr. Annette Oxenius, Swiss Federal Institute of Technology, Institute for Microbiology, 8092 Zurich, Switzerland; or Dr. Martin F. Bachmann, Cytos Biotechnology AG, Wagistrasse 25, 8952 Zurich-Schlieren, Switzerland. E-mail addresses: annette.oxenius{at}micro.biol.ethz.ch and martin.bachmann{at}cytos.com Back

3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; VLP, virus-like particle; DC, dendritic cell; LN, lymph node. Back

Received for publication April 20, 2004. Accepted for publication June 10, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Kaech, S. M., E. J. Wherry, R. Ahmed. 2002. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2:251.[Medline]
  2. Zinkernagel, R. M., M. F. Bachmann, T. M. Kundig, S. Oehen, H. Pirchet, H. Hengartner. 1996. On immunological memory. Annu. Rev. Immunol. 14:333.[Medline]
  3. Doherty, P. C., S. Hou, R. A. Tripp. 1994. CD8+ T-cell memory to viruses. Curr. Opin. Immunol. 6:545.[Medline]
  4. Sallusto, F., A. Lanzavecchia. 2001. Exploring pathways for memory T cell generation. J. Clin. Invest. 108:805.[Medline]
  5. Shedlock, D. J., H. Shen. 2003. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300:337.[Abstract/Free Full Text]
  6. Sun, J. C., M. J. Bevan. 2003. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300:339.[Abstract/Free Full Text]
  7. Bourgeois, C., H. Veiga-Fernandes, A. M. Joret, B. Rocha, C. Tanchot. 2002. CD8 lethargy in the absence of CD4 help. Eur. J. Immunol. 32:2199.[Medline]
  8. Janssen, E. M., E. E. Lemmens, T. Wolfe, U. Christen, M. G. von Herrath, S. P. Schoenberger. 2003. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421:852.[Medline]
  9. Sallusto, F., D. Lenig, R. Forster, M. Lipp, A. Lanzavecchia. 1999. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708.[Medline]
  10. Wherry, E. J., V. Teichgraber, T. C. Becker, D. Masopust, S. M. Kaech, R. Antia, U. H. von Andrian, R. Ahmed. 2003. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4:225.[Medline]
  11. Bachmann, M. F., T. M. Kundig, H. Hengartner, R. M. Zinkernagel. 1997. Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without "memory T cells"?. Proc. Natl. Acad. Sci. USA 94:640.[Abstract/Free Full Text]
  12. Storni, T., F. Lechner, I. Erdmann, T. Bachi, A. Jegerlehner, T. Dumrese, T. M. Kundig, C. Ruedl, M. F. Bachmann. 2002. Critical role for activation of antigen-presenting cells in priming of cytotoxic T cell responses after vaccination with virus-like particles. J. Immunol. 168:2880.[Abstract/Free Full Text]
  13. Storni, T., C. Ruedl, K. Schwarz, R. A. Schwendener, W. A. Renner, M. F. Bachmann. 2004. Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J. Immunol. 172:1777.[Abstract/Free Full Text]
  14. Altman, J. D., P. A. Moss, P. J. Goulder, D. H. Barouch, M. G. McHeyzer-Williams, J. I. Bell, A. J. McMichael, M. M. Davis. 1996. Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94.[Abstract/Free Full Text]
  15. Horner, A. A., S. K. Datta, K. Takabayashi, I. M. Belyakov, T. Hayashi, N. Cinman, M. D. Nguyen, J. H. Van Uden, J. A. Berzofsky, D. D. Richman, E. Raz. 2001. Immunostimulatory DNA-based vaccines elicit multifaceted immune responses against HIV at systemic and mucosal sites. J. Immunol. 167:1584.[Abstract/Free Full Text]
  16. Cho, H. J., K. Takabayashi, P. M. Cheng, M. D. Nguyen, M. Corr, S. Tuck, E. Raz. 2000. Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. Nat. Biotechnol. 18:509.[Medline]
  17. Diebold, S. S., T. Kaisho, H. Hemmi, S. Akira, E. S. C. Reis. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529.[Abstract/Free Full Text]
  18. Heil, F., H. Hemmi, H. Hochrein, F. Ampenberger, C. Kirschning, S. Akira, G. Lipford, H. Wagner, S. Bauer. 2004. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303:1526.[Abstract/Free Full Text]
  19. Schwarz, K., T. Storni, V. Manolova, A. Didierlaurent, J. C. Sirard, P. Rothlisberger, M. F. Bachmann. 2003. Role of Toll-like receptors in costimulating cytotoxic T cell responses. Eur. J. Immunol. 33:1465.[Medline]
  20. Woling, P., M. Betts, R. Koup, A. Oxenius. 2004. Immediate cytotoxicity but degranulation distinguishes effector and memory subsets of CD8+ T cells. J. Exp. Med. 199:925.[Abstract/Free Full Text]



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L. Jing, T. M. Chong, B. Byrd, C. L. McClurkan, J. Huang, B. T. Story, K. M. Dunkley, L. Aldaz-Carroll, R. J. Eisenberg, G. H. Cohen, et al.
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V. Y. Taraban, T. F. Rowley, D. F. Tough, and A. Al-Shamkhani
Requirement for CD70 in CD4+ Th Cell-Dependent and Innate Receptor-Mediated CD8+ T Cell Priming.
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Early establishment of diverse T cell receptor profiles for influenza-specific CD8+CD62Lhi memory T cells
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N. D. Jones, M. Carvalho-Gaspar, S. Luo, M. O. Brook, L. Martin, and K. J. Wood
Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help
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Innate signals compensate for the absence of PKC-{theta} during in vivo CD8+ T cell effector and memory responses
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M. F. Bachmann, P. Wolint, K. Schwarz, and A. Oxenius
Recall Proliferation Potential of Memory CD8+ T Cells and Antiviral Protection
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M. F. Bachmann, P. Wolint, K. Schwarz, P. Jager, and A. Oxenius
Functional Properties and Lineage Relationship of CD8+ T Cell Subsets Identified by Expression of IL-7 Receptor {alpha} and CD62L
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