ORCID Profile
0000-0002-4299-9479
Current Organisations
IT University of Copenhagen
,
Københavns Universitet
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Publisher: American Society for Microbiology
Date: 15-12-2000
DOI: 10.1128/JVI.74.24.11690-11696.2000
Abstract: The recall of CD8 + T-cell memory established by infecting H-2 b mice with an H1N1 influenza A virus provided a measure of protection against an extremely virulent H7N7 virus. The numbers of CD8 + effector and memory T cells specific for the shared, immunodominant D b NP 366 epitope were greatly increased subsequent to the H7N7 challenge, and though lung titers remained as high as those in naive controls for 5 days or more, the virus was cleared more rapidly. Expanding the CD8 + memory T-cell pool ( .5 to %) by sequential priming with two different influenza A viruses (H3N2→H1N1) gave much better protection. Though the H7N7 virus initially grew to equivalent titers in the lungs of naive and double-primed mice, the replicative phase was substantially controlled within 3 days. This tertiary H7N7 challenge caused little increase in the magnitude of the CD8 + D b NP 366 + T-cell pool, and only a portion of the memory population in the lymphoid tissue could be shown to proliferate. The great majority of the CD8 + D b NP 366 + set that localized to the infected respiratory tract had, however, cycled at least once, though recent cell ision was shown not to be a prerequisite for T-cell extravasation. The selective induction of CD8 + T-cell memory can thus greatly limit the damage caused by a virulent influenza A virus, with the extent of protection being directly related to the number of available responders. Furthermore, a large pool of CD8 + memory T cells may be only partially utilized to deal with a potentially lethal influenza infection.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-07-1999
Abstract: The virus-specific CD8 + T cell response has been analyzed through the development, effector, and recovery phases of primary and secondary influenza pneumonia. Apparently, most, if not all, memory T cells expressing clonotypic receptors that bind a tetrameric complex of influenza nucleoprotein (NP) 366–374 peptide+H-2D b (NPP) are induced to ide 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 influenced by intercurrent infection.
Publisher: Annual Reviews
Date: 04-2000
DOI: 10.1146/ANNUREV.IMMUNOL.18.1.561
Abstract: The cellular dynamics of the immune system are complex and difficult to measure. Access to this problematic area has been greatly enhanced by the recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) for the direct staining of freshly isolated, antigen-specific CD8 + T cells. Analysis to date with both naturally acquired and experimentally induced infections has established that the numbers of virus-specific CD8 + T cells present during both the acute and memory phases of the host response are more than tenfold in excess of previously suspected values. The levels are such that the virus-specific CD8 + set is readily detected in the human peripheral blood lymphocyte compartment, particularly during persistent infections. Experimentally, it is now possible to measure the extent of cycling for tetramer + CD8 + T cells during the acute and memory phases of the host response to viruses. Dissection of the phenotypic, functional, and molecular ersity of CD8 + T cell populations has been greatly facilitated. It is hoped it will also soon be possible to analyze CD4 + T cell populations in this way. 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.
Publisher: American Society for Microbiology
Date: 15-10-2000
DOI: 10.1128/JVI.74.20.9762-9765.2000
Abstract: Optimal expansion of influenza virus nucleoprotein (D b NP 366 )-specific CD8 + T cells following respiratory challenge of naive Ig −/− μMT mice was found to require CD4 + T-cell help, and this effect was also observed in primed animals. Absence of the CD4 + population was consistently correlated with diminished recruitment of virus-specific CD8 + T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8 + set generated during the recall response in Ig −/− mice primed at least 6 months previously showed a normal profile of gamma interferon production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4 + T-cell response. Both the magnitude and the localization profiles of virus-specific CD8 + T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4 + T cells.
Publisher: Proceedings of the National Academy of Sciences
Date: 27-04-1999
Abstract: The lack of B cells and antibody does not prevent mice from dealing effectively with a pathogenic γ-herpesvirus. Both CD4 + and CD8 + T cells contribute to the control of virus replication in the respiratory tract, with the depletion of either lymphocyte subset leading to increased titers in the lung. However, the further neutralization of IFN-γ diminishes the effectiveness of the CD4 + T cell response and causes substantially increased mortality. Experiments with bone marrow radiation chimeras indicate that the immune CD4 + effectors operate optimally when there is the potential for direct interaction with virus-infected targets expressing MHC class II glycoproteins, suggesting that the IFN-γ produced by these lymphocytes is functioning at short range. The numbers of latently infected cells in the spleens of carrier mice are also significantly increased by the concurrent depletion of both the CD4 + population and IFN-γ. These experiments raise the possibility that the defective control of intercurrent γ-herpesvirus infections in patients with AIDS not only is due solely to the absence of helper T cells but also reflects the loss of an important set of CD4 + effectors.
Publisher: The Royal Society
Date: 29-04-2001
Abstract: The murine γ–herpesvirus 68 (MHV–68) provides a unique experimental model for dissecting immunity to large DNA viruses that persist in B lymphocytes. The analysis is greatly facilitated by the availability of genetically disrupted (–/–) mice that lack key host–response elements, and by the fact that MHV–68 is a lytic virus that can readily be manipulated for mutational analysis. The mutant virus strategy is being used, for ex le, to characterize the part played in vivo by an MHV–68–encoded chemokine–binding protein that may ultimately find an application in human therapeutics. Experiments with various –/– mice and monoclonal antibody depletion protocols have shown very clearly that type I interferons (IFNs) are essential for the early control of MHV–68 replication, while CD4 + T cells producing IFN–γ function to limit the consequences of viral persistence. Virus–specific CD8 + effectors acting in the absence of the CD4 + subset seem initially to control the lytic phase in the lung following respiratory challenge, but are then unable to prevent the reactivation of replicative infection in epithelia and the eventual death of CD4 + T–cell–deficient mice. This could reflect the fact that the interaction between the CD8 + T cells and the virus–infected targets is partially compromised by the MHV–68 K3 protein, which inhibits antigen presentation by MHC class I glycoproteins. Immunization strategies focusing on the CD8 + T–cell response to epitopes expressed during the lytic phase of MHV–68 infection can limit virus replication, but are unable to prevent the establishment of latency. Other experiments with mutant viruses also suggest that there is a disconnection between lytic MHV–68 infection and latency. The massive nonspecific immunoglobulin response and the dramatic expansion of Vβ4 + CD8 + T cells, which is apparently MHC independent, could represent some sort of ‘smoke screen’ used by MHV–68 to subvert immunity. Although MHV–68 is neither Epstein–Barr virus nor human herpesvirus–8, the results generated from this system suggest possibilities that may usefully be addressed with these human pathogens. 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.
Location: United States of America
No related grants have been discovered for Jan Christensen.