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Sections of Infectious Diseases and Immunobiology, Yale University School of Medicine, New Haven, CT 06511
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD8+ CTL often play a major role in immunity to viral and intracellular bacterial infections (2). CTL recognize pathogen-derived peptide epitopes presented by MHC class I molecules on the surface of infected cells (3, 4), resulting in cytolytic destruction of the infected cell (5) and, potentially, direct killing of the pathogen (6). The generation and maintenance of specific CD8+ memory T cells is crucial for the development of effective protective immunity against many intracellular pathogens (2, 7). The similarity of memory and effector TCR repertoires suggests that memory T cells derive from effectors by a stochastic rather than selective mechanism (8, 9, 10, 11, 12). Other studies also suggest that CD8+ memory T cells are posteffector T cells, although this has not been conclusively demonstrated (1, 13). A recent study using an approach to "mark" genes that have been transiently induced indicates that memory T cells have a history of expressing genes associated with effector T cells. However, only a subset of effector T cells was maintained as memory T cells, and these were detectable during primary infection (14). These findings suggest that memory T cells represent a subset of the effector T cell population that is generated during the acute, primary immune response. The mechanisms that promote the development and expansion of early memory T cells and the factors that result in increased sensitivity and rapidity of memory T cell activation (15, 16) remain unknown.
The role of Ag during in vivo T cell expansion and memory T cell generation is poorly understood. Although Ag is required for T cell priming, long-term persistence of Ag-specific CD8+ memory T cell populations is Ag-independent (17). Indeed, Ag-independent stimulation of memory T cell populations has been discussed as an important mechanisms for the maintenance of T cell memory (18). Recent studies demonstrate that memory T cells divide in the periphery in the absence of MHC molecules (19, 20), providing further evidence for Ag-independent proliferation of Ag-specific memory T cells. Ag-independent "bystander" activation of T lymphocytes has been proposed in the context of viral infections that induce massive populations of activated T lymphocytes, and the ability of type 1 IFN to play a role in this process has been demonstrated (21). However, more recent studies have demonstrated that most activated T cells after viral infection are Ag-specific and that bystander activation accounts for few activated T cells (22, 23). After in vivo T cell priming, Ag-specific T cell populations expand, plateau, and then contract into long-term memory populations. The size of memory T cell populations correlates with the T cell burst size (12, 24), suggesting that the processes that drive in vivo T cell expansion also influence memory T cell development. The relative importance of pathogen-derived Ag presentation as opposed to infection-induced inflammation in determining in vivo T cell expansion kinetics and memory generation is unknown. Although some studies indicate that Ag-independent expansion may be an important feature of in vivo T cell responses (25), direct evidence for this is lacking.
We have used murine infection with Listeria monocytogenes to study pathogen-specific T cell responses in vivo. Mice infected i.v. with a sublethal dose of this Gram-positive, intracellular bacterium rapidly clear the pathogen and develop long-lasting immunity, which is predominantly mediated by CD8+ T cells (26, 27). Four different Listeria epitopes that are presented by the H2-Kd MHC class Ia molecule have been identified (12, 28, 29), and the kinetics of epitope generation and presentation (28) and the in vivo kinetics of the T cell response have been measured (10, 25, 30). The immunodominant epitopes LLO91–99 (listeriolysin O)4 (derived from the secreted virulence factor listeriolysin (31)) and p60217–225 (derived from the mureine hydrolase p60 (32)) elicit large epitope-specific T cell populations. MHC-tetramer reagents and mutant L. monocytogenes strains, which are fully virulent yet lack distinct immunodominant epitopes, have been exploited to analyze in vivo T cell responses to this bacterial infection (25, 33).
In this study, we investigated the roles of Ag presentation and the inflammatory response induced by bacterial infection in promoting the in vivo expansion of Ag-specific T cell populations and in the generation of T cell memory. We find that effector T lymphocyte populations that are still responding to primary L. monocytogenes infection can be induced to undergo prolonged in vivo division by inflammatory stimuli in the presence but also in the absence of cognate Ag. However, in contrast to stimulation with additional Ag, expansion that is induced by inflammation alone does not result in the enhancement of memory T cell populations. Remarkably, the duration of T cell expansion elicited by reinfection during the primary immune response is identical with a typical memory response, suggesting that the ability to mount a memory T cell response is already established before the completion of the primary immune response. In concordance with work in other infectious systems, we do not find evidence for Ag-independent bystander activation of memory T cell populations. These studies demonstrate that in vivo expansion of Ag-specific effector T cell populations can be promoted by multiple factors but that the presence of Ag is critical for the generation of memory T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Wild-type L. monocytogenes 10403s (obtained from Daniel Portnoy, University of California, Berkeley, CA) and the L. monocytogenes LLO92ser mutant strain (mutation of the tyrosine in position 92 of listeriolysin to a serine (33)) were grown in brain heart infusion broth. For primary infection, 2000 L. monocytogenes were injected into the tail veins of 8- to 10-wk-old mice. Reimmunization was performed by i.v. injection of 100,000 L. monocytogenes 5 wk after primary infection. For the early rechallenge experiments, naive mice were first infected with 2000 L. monocytogenes before a second injection with 1 x 106 bacteria 6 days later. Bacterial numbers per infected organ were determined by plating out serial dilution of homogenate on brain heart infusion broth agarose as descibed (34).
Generation and purification of H2-Kd tetramers
Tetrameric H2-Kd/LLO91–99 and H2-Kd/p60217–225 complexes were generated as recently described (10, 35). Briefly, recombinant H2-Kd heavy chain and ß2-microglobulin were expressed as insoluble inclusion bodies in Escherichia coli and were further purified. The H2-Kd heavy chain molecule was mutated to remove the transmembrane and cytosolic domain and to add a specific biotinylation site at the C terminus (36). Purified proteins were refolded in vitro in the presence of high concentrations of synthetic peptide (Research Genetics, Huntsville, AL) to form stable and soluble MHC/peptide complexes (37). Complexes were purified by gel filtration over a Superdex 200 HR column (Pharmacia, Piscataway, NJ) and specifically biotinylated in vitro by adding the enzyme BirA (Avidity), d-biotin, and ATP. After further purification, biotinylated MHC/peptide complexes were multimerized with streptavidin-PE (SA-PE; Molecular Probes, Eugene, OR). Tetrameric complexes were purified by gel filtration and stored at 2–5 mg/ml at 4°C in PBS (pH 8.0) containing 0.02% sodium azide, 1 µg/ml pepstatin, 1 µg/ml leupeptin, and 0.5 mM EDTA. Throughout the presented studies, the reagents were frequently tested on Listeria-specific T cell lines to document staining capacity and signal intensity.
Preparation of splenocytes
Spleens were removed at various time points after primary
infection or reinfection with L. monocytogenes. Splenocytes
were harvested by dissociation through a wire mesh and lysis of
erythrocytes with ammonium chloride and were subsequently
resuspended in RP10+, which consists of RPMI
1640 (Life Technologies, Rockville, MD) supplemented with 10% FCS,
L-glutamine, HEPES (pH 7.5), 2-ME, penicillin
(100 U/ml), streptomycin (100 µg/ml), and gentamicin (50 µg/ml).
For the recall experiments using wild-type and
LLO92ser L. monocytogenes, splenocytes were
positively enriched for CD8+ T cells using
magnetically activated cell sorting (MACS), anti-CD8
microbeads (clone 53-6.7), and type LS columns (all from
Miltenyi, Bergisch Gladbach, Germany). Because this procedure also
enriches for dead cells in the preparations (see Fig. 2
), we modified
our method in subsequent experiments by negatively enriching
CD8+ T cells by depleting splenocytes with
anti-CD4 (GK1.4) and anti-MHC class II (TIB120) mAbs and
anti-rat IgG microbeads (Miltenyi).
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Epitope-specific T cell populations were detected with
PE-conjugated, tetrameric MHC/peptide complexes and concurrently
stained for other surface molecules using directly conjugated mAbs as
described previously (10, 25, 30). Briefly, after blocking
with unconjugated streptavidin (0.5 mg/ml; Molecular Probes) and
Fc-block (PharMingen, San Diego, CA), 
5 x
105 CD8+-enriched cells
were incubated in FACS staining buffer (PBS (pH 7.45), 0.5% BSA, and
0.02% sodium azide) for 1 h on ice in the presence of saturating
concentrations of tetramer reagents (0.25–0.5 mg/ml) and the various
mAbs. Subsequently, cells were washed three times in staining buffer
and then fixed in 1% paraformaldehyde/PBS (pH 7.45). Flow cytometry
was performed using a FACSCalibur, collecting 200,000
CD8+ events; data were further analyzed with
CellQuest software (Becton Dickinson, Mountain View, CA). The following
mAbs were used (all obtained from PharMingen): CyChrome-conjugated
anti-CD8 (clone 53-6.7) and FITC-conjugated anti-CD62L
(clone MEL-14).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several epitopes that are recognized by CD8+
CTL during infection of mice with the intracellular bacterium L.
monocytogenes have been identified. Four Listeria
epitopes (LLO91–99,
p60217–225, p60449–457,
and mpl84–92) are recognized in the context of
the H2-Kd MHC class Ia molecule. Two of these
epitopes, LLO91–99 and
p60217–225, induce relatively large,
immunodominant T cell responses (12, 25). As shown in Fig. 1, infection of naive BALB/c mice with
L. monocytogenes results in an initial increase of the
number of bacteria in the spleen until day 3, when a rapid, T
cell-mediated clearance phase begins. Similar kinetics for bacterial
growth and clearance are seen in the livers of infected mice. Unlike
many viral infections, which cause prolonged or chronic infections,
L. monocytogenes is completely cleared from the infected
mouse, usually within 6–7 days after primary infection. Reinfection
with much higher bacterial doses results in very limited infections
with viable bacteria detectable only on the first day after bacterial
inoculation. Using MHC tetramers complexed with L.
monocytogenes epitopes, we found that the expansion kinetics of
H2-Kd-restricted Listeria-specific T
cell populations specific for different peptides are similar during
primary and recall L. monocytogenes infections, peaking 7–8
days after primary infection and 5 days after recall infection (Fig. 1). The synchronous in vivo expansion of T cells specific for the
different L. monocytogenes epitopes is surprising because
these peptides are present in vastly different amounts and have
dramatically different stabilities.
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Synchrony of in vivo T cell responses suggests that factors other
than Ag determine the in vivo kinetics of T cell expansion and entry
into the memory compartment. To investigate the influence of
inflammatory factors produced during bacterial infection on the
duration of in vivo T cell expansion, we infected mice with a fully
virulent strain of L. monocytogenes that lacks the
immunodominant LLO91–99 epitope
(33). We first determined the effect of infection with
L. monocytogenes lacking LLO91–99 on
established memory T cell populations. The in vivo role and influence
of inflammatory stimuli on memory T cells remains controversial
(21, 38). As shown in Fig. 2
, recall infection with wild-type
L. monocytogenes results in rapid and massive expansion of
LLO91–99-specific T cell populations, accounting
for 10–20% of CD8+ T cells, and an increase in
the frequency of p60217–225-specific T cells,
accounting for 2% of CD8+ T cells.
Although recall infection with L. monocytogenes
LLO92ser induces normal activation and expansion
of p60217–225-specific T cell populations,
LLO91–99-specific T cells do not increase
in number and do not undergo phenotypic changes characteristic of
activation. Thus, the ratio of CD62Lhigh to
CD62Llow on
LLO91–99-specific T cells remains constant (Fig. 2) and there are no detectable changes on forward light scatter (FSC)
profiles (Fig. 3) or on the level of
surface CD8 expression (Fig. 3). Taken together, these data indicate
that bystander activation of LLO91–99-specific
memory T cells is not detectable during recall responses to L.
monocytogenes infection.
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Although inflammation induced by bacterial infection does not
activate resting memory T cells, we wanted to determine whether
bacterial infection in the absence of Ag can promote the in vivo
expansion of activated effector T cells. Therefore, we reinfected mice
6 days after primary infection with wild-type L.
monocytogenes with a high dose of either wild-type bacteria or
L. monocytogenes LLO92ser. Without
reinfection, the expansion of the
LLO91–99-specific T cell populations terminates
7–8 days after bacterial inoculation, which is also reflected by a
rapid loss of blasting cells as measured by FSC. However, in mice
challenged with L. monocytogenes
LLO92ser,
LLO91–99-specific T cells continued to increase
in frequency for several days (Figs. 4
and 5). As determined by FSC profiles,
Ag-specific T cells continued to blast on the seventh day after primary
infection (Fig. 4), resulting in an increase in the frequency (Fig. 4)
and absolute number (Fig. 5) of
LLO91–99-specific T cells. This Ag-independent
in vivo expansion of LLO91–99-specific T cells
is followed by a rapid contraction phase. Taken together, these data
demonstrate that accentuated inflammatory responses during the terminal
phases of the primary T cell response are capable of promoting further
T cell expansion that does not depend upon the presence of Ag.
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Epitope presence and memory T cell generation
Reinfection of mice during the primary immune response with
epitope-knockout and wild-type L. monocytogenes both induce
the further expansion of LLO91–99-specific T
cell populations, but the consequences for memory T cell generation are
quite different (Figs. 4 and 5). The initial expansion of
LLO91–99-specific T cells after reinfection with
L. monocytogenes LLO92ser is followed by a
dramatic contraction phase, leaving low numbers of
LLO91–99-specific memory T cells. These data
indicate that the correlation between the effector T cell burst
magnitude and the size of memory T cell populations is not maintained
when T cells are induced to undergo increased expansion in the absence
of Ag. Reinfection with wild-type L. monocytogenes
results in enhanced expansion, and the
LLO91–99-specific memory T cell frequency is
substantially increased (Figs. 5 and 6A). Thus, Ag presentation
appears to be essential for enhanced generation of memory T cells.
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B, mice previously immunized with wild-type L.
monocytogenes alone develop a normal memory response upon
reinfection; this response is manifested by massive expansion of
LLO91–99- and
p60217–225-specific T cells (also see Fig. 2). Similarly, L. monocytogenes-immunized mice that received
a second dose of bacteria 6 days after primary infection also developed
normal LLO91–99- and
p60217–225-specific memory responses after
reinfection 5 wk later. In contrast, mice that received a primary
infection with wild-type L. monocytogenes and then a second
dose of LLO91–99-deficient L.
monocytogenes 6 days later mounted a somewhat smaller
LLO91–99-specific response upon reinfection 5 wk
later. This result further supports the conclusion that
inflammation-driven effector T cell expansion does not increase memory
T cell populations. Indeed, our results suggest that
inflammation-driven expansion in the absence of Ag may diminish the
size or responsiveness of memory T cell populations. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The development of new techniques to identify epitope-specific T cells directly ex vivo has permitted detailed analyses of normal T cell response dynamics (23, 30, 35, 41). As demonstrated here and in previous studies, the in vivo kinetics of T cell populations that differ in specificity are often synchronized (23, 25), a finding that is particularly striking during the recall infection with L. monocytogenes. Although the Ags for the four known H2-Kd-restricted Listeria epitopes are expressed by the bacterium in very different amounts and the epitopes are processed in infected cells with different kinetics and form MHC/peptide complexes with markedly different half-lives (28), the T cell kinetics are very similar. This finding suggests that factors other than epitope prevalence determine the in vivo kinetics of T cell expansion.
What effects do inflammatory stimuli have on epitope-specific T cell populations in the absence of Ag? To address this question, we used a mutant strain of L. monocytogenes that is fully virulent but does not produce the immundominant H2-Kd-restricted epitope LLO91–99 (33). Using MHC-tetramer staining we demonstrate that LLO91–99-specific memory T cells are not activated by L. monocytogenes infection if LLO91–99 is not presented. LLO91–99-specific memory T cells do not increase in number and do not undergo phenotypic changes during the course of reinfection if the specific epitope is not present. These findings confirm the results of other studies that showed that Ag-independent "bystander activation" of memory T cells is a rare event that is unlikely to be crucial for the maintenance of T cell memory (22, 23, 38).
In contrast to our findings with memory T cells, early reinfection with L. monocytogenes lacking LLO91–99 promoted further in vivo expansion of effector T cells specific for LLO91–99. This finding indicates that activated effector T cell populations respond to the in vivo inflammation induced by L. monocytogenes infection in the absence of additional Ag presentation. Our experiments do not identify the specific factors mediating this Ag-independent T cell expansion, but they demonstrate that inflammation induced by bacterial infection serves as a potent stimulus for effector T cell proliferation.
T cell activation is accompanied by transient surface expression of the high-affinity IL-2 and IL-15 receptors, promoting T cell proliferation upon exposure to these cytokines (42). From in vitro studies it is clear that IL-2 in the absence of Ag can promote limited effector T cell proliferation even in the absence of TCR-mediated signals (43). Thus, it is possible that early reinfection with L. monocytogenes induces the production of IL-2 and perhaps other growth-promoting cytokines, which drive further proliferation of effector T cells. Alternatively, it is possible that bacterial products such as lipoteichoic acids or peptidoglycan directly stimulate the growth of effector T cells in an Ag-independent fashion (44). Another possibility is that early reinfection provides antiapoptotic stimuli that promote effector T cell survival (45).
It is interesting that reinfection of mice before resolution of a primary infection induces further expansion of Ag-specific T cells that kinetically approximates the typical memory response that is induced by reinfection months after the resolution of a primary infection. We have previously shown that memory T cells undergo dramatic in vivo expansion for 5 days after reinfection. Similarly, reinfection of mice 6 days after primary infection, which precedes the maximal in vivo primary T cell response by 1–2 days, results in 5 additional days of expansion. This observation suggests that the ability to mount a memory T cell response is established before the completion of the expansionary phase of the primary T cell response. This interpretation of our findings is supported by a recent study using a transgenic approach that detected potential memory T cells during the effector phase of infection (14).
The presence or absence of cognate epitope during in vivo restimulation of effector T cells has significant consequences for the development of memory T cell populations. The presentation of additional Ag increases the burst size of the effector T cell population, ultimately resulting in a substantially larger memory T cell population, as we have previously described for recall responses to L. monocytogenes infection (25). In contrast, early reinfection with L. monocytogenes LLO92ser, the strain lacking the dominant LLO91–99 epitope, results in continued expansion of LLO91–99-specific T cells and then very rapid contraction and a lower frequency of LLO91–99-specific memory T cells. Thus, effector T cell expansion that occurs in the absence of Ag does not enhance T cell memory, demonstrating that the T cell burst size does not always correlate with the size of the resulting memory population. This finding may have important implications for vaccine and adjuvant development.
It is likely that Ag and inflammatory factors collaboratively promote effector T cell proliferation and survival and that both play a role during productive in vivo T cell expansion. Our results suggest that while inflammation alone can promote in vivo T cell expansion, Ag presentation is required for the expansion of the memory compartment. On the basis of our results, we suggest that the capacity for a memory T cell response is "hard-wired" in the Ag-specific effector T cell population before the completion of the expansionary phase of the primary T cell response. Whether memory T cells constitute a distinct subpopulation of effector T cells remains unclear. It is possible that all effector T cells acquire a "memory program" that requires a TCR-mediated signal to be activated. If this is the case, then exposure of a large effector T cell population, such as the one present 6 days after primary infection, should result in a very large memory T cell response. Our results do not support this hypothesis because the "memory" response induced by reinfection during the primary T cell response is smaller than the response obtained 6 wk after the resolution of infection. Our results are more consistent with the idea that a distinct subset of the total effector T cell population is capable of further expansion upon re-exposure to Ag.
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Footnotes |
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2 Current address: Institute for Microbiology, Immunology and Hygiene, Technical University Munich, Trogerstraße 24, 81675 Munich, Germany
3 Address correspondence and reprint requests to Dr. Eric G. Pamer, Sections of Infectious Diseases and Immunobiology, Yale University School of Medicine, Laboratory of Clinical Investigation 803, 333 Cedar Street, New Haven, CT 06520.
4 Abbreviations used in this paper: LLO, listeriolysin O; FSC, forward light scatter.
Received for publication January 6, 2000. Accepted for publication February 7, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß with an antigenic Tax peptide from human T lymphotropic virus type 1 and the class I MHC molecule HLA-A2. J. Immunol. 157:5403.[Abstract]
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M. J. Skeen, E. P. Rix, M. M. Freeman, and H. K. Ziegler Exaggerated Proinflammatory and Th1 Responses in the Absence of gamma /delta T Cells after Infection with Listeria monocytogenes Infect. Immun., December 1, 2001; 69(12): 7213 - 7223. [Abstract] [Full Text] [PDF]
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P. Wong and E. G. Pamer Cutting Edge: Antigen-Independent CD8 T Cell Proliferation J. Immunol., May 15, 2001; 166(10): 5864 - 5868. [Abstract] [Full Text] [PDF]
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M. Ahmadzadeh, S. F. Hussain, and D. L. Farber Heterogeneity of the Memory CD4 T Cell Response: Persisting Effectors and Resting Memory T Cells J. Immunol., January 15, 2001; 166(2): 926 - 935. [Abstract] [Full Text] [PDF]
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G. Lertmemongkolchai, G. Cai, C. A. Hunter, and G. J. Bancroft Bystander Activation of CD8+ T Cells Contributes to the Rapid Production of IFN-{{gamma}} in Response to Bacterial Pathogens J. Immunol., January 15, 2001; 166(2): 1097 - 1105. [Abstract] [Full Text] [PDF]
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 A. Lanzavecchia and F. Sallusto Dynamics of T Lymphocyte Responses: Intermediates, Effectors, and Memory Cells Science, October 6, 2000; 290(5489): 92 - 97. [Abstract] [Full Text]
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, LLO91–99-specific T cells per spleen;
, p60217–225-specific T cells per spleen.
, reinfection with the L.
monocytogenes lacking LLO91–99.
, reinfection with 1
x 106 wild-type L. monocytogenes
(L.m-wt) on 6 days after primary infection; 
,
reinfection on day 6 with 1 x 106 epitope knockout
L. monocytogenes (LLO92ser).
LLO91–99- and p60217–225-specific T cell
populations were identified by H2-Kd tetramer staining, and
absolute numbers were calculated. Mean values of three to four mice per
group and SD are plotted. A, Absolute numbers of
LLO91–99-specific memory T cell populations in the spleen
5 wk after primary infection. B,
LLO91–99-specific T cell populations in the spleen 5
days after recall infection with 100,000 wild-type L.
monocytogenes. C,
p60217–225-specific T cell populations in spleens 5 days
after recall infection, as in B.