Compromised Influenza Virus-Specific CD8+-T-Cell Memory in CD4+-T-Cell-Deficient Mice (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
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.
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.
Journal of Virology, 2003
The consequences for the long-term maintenance of virus-specific CD8 ؉ -T-cell memory have been analyzed experimentally for sequential respiratory infections with readily eliminated (influenza virus) and persistent (gammaherpesvirus 68 [␥HV68]) pathogens. Sampling a broad range of tissue sites established that the numbers of CD8 ؉ T cells specific for the prominent influenza virus D b NP 366 epitope were reduced by about half in mice that had been challenged 100 days previously with ␥HV68, though the prior presence of a large CD8 ؉ D b NP 366 ؉ population caused no selective defect in the ␥HV68-specific CD8 ؉ K b p79 ؉ response. Conversely, mice that had been primed and boosted to generate substantial ␥HV68-specific CD8 ؉ D b p56 ؉ populations did not show any decrease in prevalence for this set of CD8 ؉ memory cytotoxic T lymphocytes (CTL) at 200 days after respiratory exposure to an influenza A virus. However, in both experiments, the total magnitude of the CD8 ؉ -T-cell pool was significantly diminished in those that had been infected with ␥HV68 and the influenza A virus. The broader implications of these findings, especially under conditions of repeated exposure to unrelated pathogens, are explored with a mathematical model which emphasizes that the immune effector and memory "phenome" is a function of the overall infection experience of the individual.
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.
Role of Memory T Cells in Influenza Viral Infection
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2008
The major role of memory T cells is to ensure protection upon re-exposure to pathogens through rapid clonal proliferation and functional activation. This immunity usually persists for periods which can extend for over 60 years. These memory T cells are generated during acute viral infections. In the context of influenza viral infection, the presence of neutralizing antibodies against influenza virus proteins provides the first line of defense that prevents viral colonization and replication. Long-lasting humoral protective immunity is also needed for protection. However, antibodies against one subtype are usually inefficient in providing protection against other subtypes in humans. Major cytotoxic T-cell responses are usually targeted against conserved internal viral proteins. Moreover, the generated CTL responses are cross-reactive between influenza subtypes. In this review, we will discuss the generation and persistence of memory T cells and the role they play during influenza viral infection. An overview of new vaccine approaches aiming at the development of protective T-cell immune memory against influenza infection will also be provided.
The Journal of Immunology, 2010
Naive and recall CD4 + T cell responses were probed with recombinant influenza Aviruses incorporating the OVA OT-II peptide. The extent of OT-II-specific CD4 + T cell expansion was greater following primary exposure, with secondary challenge achieving no significant increase in numbers, despite higher precursor frequencies. Adoptive transfer experiments with OT-II TCR-transgenic T cells established that the predominant memory set is CD62L hi , whereas the CD62L lo precursors make little contribution to the recall response. Unlike the situation described by other investigators, in which the transfer of very large numbers of in vitro-activated CD4 effectors can modify the disease process, providing CD62L hi or CD62L lo OT-II-specific T cells at physiological levels neither enhanced virus clearance nor altered clinical progression. Some confounding effects of the transgenic model were observed, with decreasing primary expansion efficiency correlating with greater numbers of transferred cells. This was associated with increased levels of mRNA for the proapoptotic molecule Bim in cells recovered following high-dose transfer. However, even with very low numbers of transferred cells, memory T cells did not expand significantly following secondary challenge. A similar result was recorded in mice primed and boosted to respond to an endogenous IA b-restricted epitope derived from the influenza virus hemagglutinin glycoprotein. Depletion of CD8 + T cells during secondary challenge generated an increased accumulation of OT-II-specific T cells but only at the site of infection. Taken together, significant expansion was not a feature of these secondary influenza-specific CD4 T cell responses and the recall of memory did not enhance recovery.
Immunological Reviews, 2006
We have outlined the carefully orchestrated process of CD4 + T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4 + T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multi-faceted roles of CD4 + effector and memory T