Quantitative Analysis of Long-Term Virus-Specific CD8+-T-Cell Memory in Mice Challenged with Unrelated Pathogens (original) (raw)
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Compromised Influenza Virus-Specific CD8+-T-Cell Memory in CD4+-T-Cell-Deficient Mice
Journal of Virology, 2002
The primary influenza A virus-specific CD8 ؉ -T-cell responses measured by tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL) lymphocyte populations were similar in magnitude for conventional I-A b؉/؉ and CD4 ؉ -T-cell-deficient I-A b؊/؊ mice. Comparable levels of virus-specific cytotoxic-Tlymphocyte activity were detected in the inflammatory exudate recovered by BAL following challenge. However, both the size of the memory T-cell pool and the magnitude of the recall response in the lymphoid tissues (but not the BAL specimens) were significantly diminished in mice lacking the CD4 ؉ subset. Also, the rate of virus elimination from the infected respiratory tract slowed at low virus loads following challenge of naïve and previously immunized I-A b؊/؊ mice. Thus, though the capacity to mediate the CD8 ؉ -T-cell effector function is broadly preserved in the absence of concurrent CD4 ؉ -T-cell help, both the maintenance and recall of memory are compromised and the clearance of residual virus is delayed. These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection.
Memory and recall CD8+ T cell responses to the influenza A viruses
International Congress Series, 2001
The recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) enables, for the first time, accurate quantitation of CD8 + T cell responses. The characteristics of the cellular immune response following primary, secondary or even tertiary challenge with serologically distinct influenza A viruses can now be understood much more clearly. The prevalence of H-2D b -restricted CD8 + memory T cells specific for the immunodominant NP 366 -374 peptide that stains with the D b NP 366 tetramer increases from undetectable levels in naïve mice, to frequencies of 0.2 -0.5% (of the CD8 + set) following i.p. exposure to an H1N1 virus. This is boosted to > 10% when these H1N1-immune mice are exposed intranasally to an H3N2 virus. Further respiratory challenge of these H1N1-or H3N2 ! H1N1-primed mice with a virulent H7N7 virus shows very clearly that the rate of virus clearance is a direct function of the size of the available CD8 + memory T cell pool. However, though established CD8 + T cell memory always provides a measure of protection against the development of clinical disease, replicative infection is still established in the face of massive numbers of virus-specific CD8 + memory T cells. The implications of these findings for immunization against both influenza and other viruses are discussed. D
In vivo proliferation of naive and memory influenza-specific CD8+ T cells
Proceedings of the National Academy of Sciences, 1999
The virus-specific CD8 ؉ T cell response has been analyzed through the development, effector, and recovery phases of primary and secondary inf luenza pneumonia. Apparently, most, if not all, memory T cells expressing clonotypic receptors that bind a tetrameric complex of inf luenza nucleoprotein (NP) 366 -374 peptide؉H-2D b (NPP) are induced to divide during the course of this localized respiratory infection. The replicative phase of the recall response ends about the time that virus can no longer be recovered from the lung, whereas some primary CD8 ؉ NPP ؉ T cells may proliferate for a few more days. The greatly expanded population of CD8 ؉ NPP ؉ memory T cells in the lymphoid tissue of secondarily challenged mice declines progressively in mean prevalence over the ensuing 100 days, despite the fact that at least some of these lymphocytes continue to cycle. The recall of cell-mediated immunity thus is characterized by massive proliferation of the antigen-specific CD8 ؉ set, whereas the extent of lymphocyte turnover in the absence of cognate peptide is variable, at a low level, and can be inf luenced by intercurrent infection.
Concurrent naive and memory CD8+ T cell responses to an influenza A virus
The Journal of …, 2001
Memory Thy-1 ؉ CD8 ؉ T cells specific for the influenza A virus nucleoprotein (NP 366 -374 ) peptide were sorted after staining with the D b NP 366 tetramer, labeled with CFSE, and transferred into normal Thy-1.2 ؉ recipients. The donor D b NP 366 ؉ T cells recovered 2 days later from the spleens of the Thy-1.2 ؉ hosts showed the CD62L low CD44 high CD69 low phenotype, characteristic of the population analyzed before transfer, and were present at frequencies equivalent to those detected previously in mice primed once by a single exposure to an influenza A virus. Analysis of CFSE-staining profiles established that resting tetramer ؉ T cells divided slowly over the next 30 days, while the numbers in the spleen decreased about 3-fold. Intranasal infection shortly after cell transfer with a noncross-reactive influenza B virus induced some of the donor D b NP 366 ؉ T cells to cycle, but there was no increase in the total number of transferred cells. By contrast, comparable challenge with an influenza A virus caused substantial clonal expansion, and loss of the CFSE label. Unexpectedly, the recruitment of naive Thy-1.2 ؉ CD8 ؉ D b NP 366 ؉ host D b NP 366 ؉ T cells following influenza A challenge was not obviously diminished by the presence of the memory Thy-1.1 ؉ CD8 ؉ D b NP 366 ؉ donor D b NP 366 ؉ set. Furthermore, the splenic response to an epitope (D b PA 224 ) derived from the influenza acid polymerase (PA 224 -233 ) was significantly enhanced in the mice given the donor D b NP 366 ؉ memory population. These experiments indicate that an apparent recall response may be comprised of both naive and memory CD8 ؉ T cells.
Journal of Virology, 2002
taining peptide immunogens was examined. The most potent synthetic immunogens for eliciting pulmonary viral-clearing responses contained peptides representing determinants for CD4 and CD8 T cells (TH and CTL peptides, respectively) together with two or four palmitic acid (Pal) groups. Inoculated in adjuvant, these Pal2or Pal4-CTL-TH lipopeptides and the nonlipidated CTL peptide induced equivalent levels of cytolytic activity in the primary effector phase of the response. The ability to recall lytic responses, however, diminished much more rapidly in CTL peptide-primed than in lipopeptide-primed mice. By 15 months postpriming, the recalled lytic activity in lipopeptide-inoculated mice remained potent, but the response induced by the CTL peptide was weak. Enumeration of specific gamma interferon-secreting CD8 T cells revealed that a greater number of these T cells had entered or remained in the memory pool in lipopeptide-primed mice, arguing for a quantitative rather than qualitative enhancement of the response on recall. Addition of either the lipid or the TH peptide to the CTL peptide was not sufficient to provide these long-lived antiviral responses, but inclusion of both components augmented the response. CD4 T cells elicited by the lipopeptides did not influence the rate of viral clearance upon challenge and most likely had a role in induction or maintenance of the memory response. It therefore appears that the lipopeptide immunogens, although not significantly superior at inducing primary effector CD8 T cells, elicit a much more effective memory population, the recall of which may account for their superiority in inducing pulmonary protection after viral challenge.
The Journal of Immunology, 2003
Kinetic studies and short pulses of injected 5-bromo-2-deoxyuridine have been used to analyze the development and renewal of peripheral CD8 ؉ memory T cells in the lungs during primary and secondary respiratory virus infections. We show that developing peripheral CD8 ؉ memory T cells proliferate during acute viral infection with kinetics that are indistinguishable from those of lymphoid CD8 ؉ memory T cells. Secondary exposure to the same virus induces a new round of T cell proliferation and extensive renewal of the peripheral and lymphoid CD8 ؉ memory T cell pools in both B cell-deficient mice and mice with immune Abs. In mice with virus-specific Abs, CD8 ؉ T cell proliferation takes place with minimal inflammation or effector cell recruitment to the lungs. The delayed arrival of CD8 ؉ memory T cells to the lungs of these animals suggests that developing memory cells do not require the same inflammatory signals as effector cells to reach the lung airways. These studies provide important new insight into mechanisms that control the maintenance and renewal of peripheral memory T cell populations during natural infections.
The Journal of Immunology, 2003
Previous studies have shown that heterologous viral infections have a significant impact on pre-existing memory T cell populations in secondary lymphoid organs through a combination of cross-reactive and bystander effects. However, the impact of heterologous viral infections on effector/memory T cells in peripheral sites is not well understood. In this study, we have analyzed the impact of a heterologous influenza virus infection on Sendai virus-specific CD8 ؉ effector/memory cells present in the lung airways. The data show a transient increase in the numbers of Sendai virus nucleoprotein 324 -332/K b -specific CD8 ؉ memory T cells in the airways of the influenza-infected mice peaking around day 4 postinfection. Intratracheal transfer studies and 5-bromo-2-deoxyuridine incorporation demonstrate that this increase is due to the recruitment of resting memory cells into the airways. In addition, the data show that these immigrating memory cells are phenotypically distinct from the resident memory T cells of the lung airways. A similar influx of nonproliferating Sendai virus nucleoprotein 324 -332/K b -specific CD8 ؉ memory T cells is also induced by a secondary (homologous) infection with Sendai virus. Together, these data suggest that inflammation can accelerate memory T cell migration to nonlymphoid tissues and is a part of the normal recall response during respiratory infections.