Concurrent naive and memory CD8+ T cell responses to an influenza A virus (original) (raw)
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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.
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.
The Journal of Infectious Diseases, 2003
We characterized the human CD8 + T cell response against influenza A viruses by a flow cytometry-based assay. Peripheral blood mononuclear cells (PBMCs) were incubated with inactivated influenza virus preparation, for 17 h, and were stained for intracellular interferon-g. Major histocompatibility complex class I-restricted memory CD8 + T cells specific for influenza antigens were detected in PBMCs from all 19 adult donors, at an average frequency of 0.39%. On average, 83% of influenza virus-specific CD8 + T cells expressed the differentiation-associated marker CD27, a percentage that is significantly higher than that of CD8 + T cells specific for pp65 of human cytomegalovirus (53%). These observations indicate that class I-restricted immunity against influenza A viruses is characterized by the persistence, after clearance of infection, of circulating antigen-specific CD8 + T cells. The different patterns of CD27 expression in influenza virus-and cytomegalovirus-specific CD8 + T cells suggest that influenza virus-specific memory and effector CD8 + T cells can be differentiated by phenotypic analysis.
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.
Journal of virology, 2000
Respiratory challenge of H-2 b mice with an H3N2 influenza A virus causes an acute, transient pneumonitis characterized by the massive infiltration of CD8 ؉ T lymphocytes. The inflammatory process monitored by quantitative analysis of lymphocyte populations recovered by bronchoalveolar lavage is greatly enhanced by prior exposure to an H1N1 virus, with the recall of cross-reactive CD8 ؉ -T-cell memory leading to more rapid clearance of the infection from the lungs. The predominant epitope recognized by the influenza virus-specific CD8 ؉ set has long been thought to be a nucleoprotein (NP 366-374 ) presented by H-2D b (D b NP 366 ). This continues to be true for the secondary H3N23H1N1 challenge but can no longer be considered the case for the primary response to either virus. Quantitative analysis based on intracellular staining for gamma interferon has shown that the polymerase 2 protein (PA 224-233 ) provides a previously undetected epitope (D b PA 224 ) that is at least as prominent as D b NP 366 during the first 10 days following primary exposure to either the H3N2 or H1N1 virus. The response to D b NP 366 seems to continue for longer, even when infectious virus can no longer be detected, but there is no obvious difference in the prevalence of memory T cells specific for D b NP 366 and D b PA 224 . The generalization that the magnitude of the functional memory T-cell pool is a direct consequence of the clonal burst size during the primary response may no longer be useful. Previous CD8 ؉ -T-cell immunodominance heirarchies defined largely by cytotoxic T-lymphocyte assays may need to be revised.
Journal of Virology, 2000
Respiratory challenge of H-2 b mice with an H3N2 influenza A virus causes an acute, transient pneumonitis characterized by the massive infiltration of CD8 ؉ T lymphocytes. The inflammatory process monitored by quantitative analysis of lymphocyte populations recovered by bronchoalveolar lavage is greatly enhanced by prior exposure to an H1N1 virus, with the recall of cross-reactive CD8 ؉ -T-cell memory leading to more rapid clearance of the infection from the lungs. The predominant epitope recognized by the influenza virus-specific CD8 ؉ set has long been thought to be a nucleoprotein (NP 366-374 ) presented by H-2D b (D b NP 366 ). This continues to be true for the secondary H3N23H1N1 challenge but can no longer be considered the case for the primary response to either virus. Quantitative analysis based on intracellular staining for gamma interferon has shown that the polymerase 2 protein (PA 224-233 ) provides a previously undetected epitope (D b PA 224 ) that is at least as prominent as D b NP 366 during the first 10 days following primary exposure to either the H3N2 or H1N1 virus. The response to D b NP 366 seems to continue for longer, even when infectious virus can no longer be detected, but there is no obvious difference in the prevalence of memory T cells specific for D b NP 366 and D b PA 224 . The generalization that the magnitude of the functional memory T-cell pool is a direct consequence of the clonal burst size during the primary response may no longer be useful. Previous CD8 ؉ -T-cell immunodominance heirarchies defined largely by cytotoxic T-lymphocyte assays may need to be revised.
Journal of Clinical Investigation, 2008
Nonstandard abbreviations used: BCL, B cell line; ELISpot, enzyme-linked immunosorbent spot; ICS, intracellular cytokine staining; M1, matrix protein 1; NA, neuraminidase; NP, nucleoprotein; PB1, polymerase basic protein 1; rVACV, recombinant vaccinia virus; SFU, spot-forming unit.