Peter Doherty

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..These peptides could be used to add a CD8+ T cell component to current antibody-focused vaccine strategies with a view to reducing the impact of infection with novel influenza A viruses...

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..Virus infections, particularly HIV, pose enormous challenges for the future. It is generally helpful to know a little of what went before...

..Part of my focus since then has been to communicate the societal value and power of science to the broader community. As my scientific life is not yet over, I confine the present historical account to the twentieth century...

..Perhaps the main lesson learned to date is that all the components of immunity are likely to be important for the control of these complex viruses...

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..Thus, the evidence to date supports a very traditional view; CD8+ T cells function mainly as killers and the CD4+ T cells as helpers in these respiratory virus infections...

..These techniques are, for the first time, putting the analysis of T-cell-mediated immunity on a quantitative basis...

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..Though these are early days and there is an enormous amount to be done, our perceptions of the shape of virus-specific cell-mediated immunity are changing rapidly...

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..These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection...

..Even "sub-optimal" TCR alpha beta pairs can operate effectively when exposed in a milieu of high virus load. Thus, TCR beta diversity is important for optimal TCR alpha beta pairing and function when TCR alpha is limiting...

..Molecular profiles identified in antigen-specific T cells at this time may thus be considered to reflect established immunologic memory and not recent CTL activation from a persistent pMHCI pool...

..Furthermore, factors that impact the quality of immunity are discussed. These factors are important considerations when evaluating the efficacy of novel vaccine strategies that target dendritic cells for eliciting cellular immunity...

..Our study demonstrates a CD4+ T cell-dependent, antiviral IgA response that is generated in the absence of B cell signaling via MHC II or CD40, and is restricted exclusively to virus-specific B cells...

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..This demonstrated the dose-sparing capacity of the SIN vector system and its ability to stimulate long-term memory responses, properties that are highly desirable in any vaccine formulation...

..These findings suggest intriguing possibilities for vaccination and, at the same time, emphasize that engineered modifications in viruses may have unintended immunological consequences...

..These experiments provide insights that may be of value for adoptive immunotherapy, where careful consideration of both the activation state and the number of effector cells is required...

..It seems that location rather than CD62Lhi/lo phenotype may be the more profitable focus for further dissection of the early establishment of T cell memory...

..This analysis thus defines how naive, effector, and memory T cells differ in cytotoxic potential and provides novel insight into the molecular signatures of effector molecules observed at various stages after infection...

..Thus, this immunodominance hierarchy is a direct function of antigen dose and T cell numbers...

..Thus, while effector gene expression can be acquired early, maturation of cytotoxic capacity requires extended differentiation...

..Therefore, the massive difference in magnitude for the secondary, although not the primary, response to these D(b)NP(366) and D(b)PA(224) epitopes cannot be considered to reflect differential TNFR2-mediated T cell editing...

..Targeting the tipDCs in this way thus offers possibilities for therapeutic intervention in the face of a catastrophic pandemic...

..Therefore, both lymphoid and tissue-resident memory CTL down-regulate cytolytic molecule transcription following virus clearance unless localized Ag is present...

..A better understanding of TCR selection and maintenance has implications for improved vaccine and immunotherapy protocols...

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..The key finding is thus that the role of TdT in ensuring enhanced diversity and the selection of private TCR repertoires promotes optimal CD8(+) T cell immunity, both within individuals and across the species as a whole...

..This review focuses on how CD8(+) T cells acquire and regulate effector functions and how the capacity to produce effector molecules is maintained into memory...

..A possible explanation is that novel, as yet undetected epitopes emerge following primary exposure to the -NP-PA deletion viruses. These findings have implications for both natural infections and vaccines...

..The approach offers novel insights into the factors determining the selection of immune repertoires, and their functional consequences for CD8(+) T cell-mediated immunity...

..Thus CTL immunity was independent of CD4+ T cells in a chronic herpesvirus infection, but was still inadequate to control virus replication...

..This cytokine imbalance is reminiscent of the clinical findings in two humans who died of H5N1/97 infection and may explain the unusual severity of the disease...

..The long-term distribution of memory T cells seemed to be essentially random...

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..Thus, the lack of prominent features in an antigenic complex of peptide and major histocompatibility complex class I is associated with a diminished spectrum of TCR usage...

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..Analysis of CTL grzA expression during influenza virus immunity has enabled a more detailed insight into the cytolytic mechanisms of virus elimination...

..It seems that the relationship between protective humoral and cellular immunity is neither simple nor readily predicted...

..Memory CD4(+) and CD8(+) T cells thus act together to limit gammaHV68 infection but are unable to provide absolute protection against a high-dose, homologous challenge...

..This suggests that VLA-1 is responsible for retaining protective memory CD8 T cells in the lung and other tissues via attachment to the extracellular matrix...

..The progress has been enormous, but there is a great deal still to be learned. A particular challenge is to use what we know for human benefit...

..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...

..Overall, these findings suggest that vaccine approaches using virus vectors to deliver an Ag may be optimized by disrupting key peptides in the normal CD8+ T cell response associated with common HLA types...

..Together, these results show clearly that the liver is not a "graveyard" for influenza virus-specific CD8+ T cells...

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..To quantify the immune response of WASP- mice to three different pathogens: influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis...

..Together, our results suggest that IL-18, but not IL-12, induces optimal, antigen-specific production of key cytokines by CD8+ T cells for the efficient clearance of influenza virus from the lungs of infected mice...

..This suggests that grzK plays an important role in CD8(+) T-cell cytotoxicity both in the presence and absence of grzA and B...

..Since CTL contribute to the success of vaccines in other model systems, an understanding of the strengths and possible limitations of these cells may be critical to future successes in the HIV-1 vaccine field...

..To explain the clustering of Th cell epitopes, we propose that localization of peptide on exposed envelope surfaces facilitates proteolytic activity and preferential peptide shuttling through the Ag processing pathway...

..Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific B-cell and T-cell responses, are reviewed...

..We discuss the advantages of developing a vaccine based on cell-mediated immune responses toward highly pathogenic influenza virus and potential problems arising from immune pressure...

..Hence, our analysis suggests that early establishment of influenza-specific memory within the CD8(+)CD62L(hi) subset preserves clonal diversity and prevents "overdominance" by a few public, or shared, clones...

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..The present analysis is the first comprehensive demonstration that IFN-gamma signaling can differentially regulate both Ag-specific CTL homeostasis in secondary lymphoid organs and trafficking to a site of virus-induced pathology...

..Furthermore, this study shows that different indicators of avidity do not necessarily provide similar information and should be used in combination to obtain an overall picture of the characteristics of TCR binding...

..1/8.2 D(d)Env(311) TCR repertoire diversity. This work further emphasizes the importance of understanding vaccine-induced CD8+ T cell responses...

..The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals...

..The remaining positions may be empty, or may be associated with a second, perhaps unrelated, peptide moiety...

..Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies...

..A greater understanding of these factors will be crucial for the development of effective vaccines in the future...

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..One example involves a comparison between the central and effector memory T cell subsets, defined on the basis of CD62L expression, and the other examines changes in the TCR repertoire over time...

..Results are consistent with the suggestion that gp120 peptide location influences antigen processing, which, in turn, influences the specificity of immunodominant T cells...

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..Thus, whereas TCR sequence (or affinity) appears to contribute substantially to the avidity profile of diverse virus-specific CD8+ populations, other mechanisms may be prominent where the TCR spectrum is more limited...

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..Thus, whereas a diverse repertoire may be important for recognition of epitope variants, its effect on the response to cognate pMHC recognition appears minimal...

..Therefore, even in CD8 T cell responses that appear to be oligoclonotypic, the total response is highly diverse...

..These studies should allow us to develop a clear, mechanistic understanding of how to promote effective CMI against the H5N1 viruses. ..

..These studies should allow us to develop a clear, mechanistic understanding of how to promote effective CMI against the H5N1 viruses. ..