Raymond M Welsh

..This subsequent change in T cell dynamics can alter patterns of immunopathology and persistence and implicates NK cells as rheostat-like regulators of persistent infections...

..1(+)CD3(-) NK cells and not to NK1.1(+)CD3(+) "NK/T" cells. This is the first evidence that control of a virus infection in vivo is mediated by a distinct NK cell subset...

..The significance of the private specificities of these repertoires is brought about under conditions of heterologous immunity and might have important consequences in anti-viral immunity and immunopathology...

..Examples are given of how the private specificities of immune responses under conditions of heterologous immunity influence the pathogenesis of murine and human viral infections...

..We suggest that the specific removal of such pathogenic epitopes from vaccines might increase their prophylactic potential, while minimizing the risk of side-effects from vaccine use...

..We propose that heterologous immunity is an important factor in resistance to and variations of human viral infections and that issues of heterologous immunity should be considered in the design of vaccines...

..Persistent infections can induce apoptotic deletions of memory T cells that are specific to the persisting virus and to previously encountered pathogens...

..We show here in Fig. 1 that a series of infections can indeed reduce the total number of memory cells, indicating that vaccination strategies need to consider this issue...

..Here we describe how T and B cell memory is generated in response to virus infections and how these cells respond when the host is infected again by similar or different viruses...

..2009; Rutishauser et al., 2009; Shin et al., 2009) indicate that the transcriptional repressor Blimp-1 promotes the development of short-lived effector cells and regulates clonal exhaustion...

..Mice previously infected with LCMV and harboring allo-specific memory T cells were refractory to the induction of tolerance to allogeneic skin grafts...

..These data suggest that distinct but overlapping cellular and molecular mechanisms control the ability of TLR agonists to block tolerance induction to hematopoietic and skin allografts in mice treated with costimulation blockade...

..In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells...

..Defining such cross-reactive networks between commonly encountered human pathogens may facilitate the design of vaccines...

..In this study, we demonstrate CD4-dependent MHC class II-restricted killing in lymphocytic choriomeningitis virus-infected mice in vivo using an in vivo cytotoxicity assay that features class II-expressing B cells as targets...

..This rapid generation of allospecific CTL activity during a viral infection preceded the peak of viral epitope-specific T cell responses, as detected by in vivo or in vitro cytotoxicity assays...

..These findings demonstrate the plasticity of the B cell subsets in virus-infected hosts and show for the first time that B cells derived exclusively from Fo B cells can effectively function in antiviral TI-2 responses...

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..This study therefore links an early virus-induced lymphopenia to a subsequent long-term loss of CD8 T cell memory and offers a new mechanism for immune deficiency during persistent viral infections...

..We conclude that rapid production of TNF-alpha can be used to quantify naive alloreactive T cells, that it is abrogated after the induction of tolerance, and that it is a potential tool to predict allograft rejection...

..We conclude that TLR signaling abrogates the effects of costimulation blockade by preventing alloreactive CD8+ T cell apoptosis through a mechanism not dependent on TNFR2 or IL-12R signaling...

..Blocking of type 1 IFN-dependent pathways in patients may improve allograft survival in the presence of exogenous TLR ligands...

..The tissue-dependent and epitope-dependent preapoptotic state correlated with reduced expression of IL-7Ralpha...

..This variability in cross-reactive T cell expansion that is unique to the individual may underlie variation in the pathogenesis of infectious diseases...

..We suggest that dissimilar cross-reactive epitopes might generate a broad, rather than a narrow, T cell repertoire if there is a lack of dominant high-affinity clones; this hypothesis is supported by computer simulation...

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..This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes...

..Thus, whereas an HP immune system is capable of mounting relatively normal acute and memory CD8 T-cell responses, the narrowing of the T-cell repertoire may reduce immune responses to subsequently encountered pathogens...

..Our findings demonstrate a protective role for NK and gammadelta T cells against naturally occurring virus-induced tumors and suggest the involvement of NKG2D-mediated mechanisms...

..These results show that frequencies of naïve and memory CD8(+) T cell precursors for whole viruses can be remarkably high...

..This indicates that virus-induced immunopathology under conditions of heterologous immunity is a function of the private specificity of the immune repertoire...

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..These results suggest that IFN-γ produced by multiple activated leukocyte populations in Fas-deficient hosts enhances resistance to some viral infections...

..A similar strategy could be used to develop reagents to analyze cross-reactive T cell responses in humans...

..This approach, therefore, formally demonstrates and quantifies a virus-induced polyclonal proliferation and differentiation of B cells, which, due to their high proportion, would mostly have BCR not specific for the virus...

..Thus, depending on the pathogen and the sequence of infection, a heterologous agent may selectively stimulate the memory pool in patterns consistent with heterologous immunity...

..These defects cannot be rescued by providing virus-specific CD4(+) T cell help, thereby substantiating the important role of Tec kinases in CD8(+) T cell signaling...

..These results suggest that PD-1 may play a negative regulatory role to control rapidly proliferating and potentially pathogenic autoreactive CD8+ T cells during homeostatic reconstitution of lymphopenic environments...

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..These results illustrate the importance of NK cell self-tolerance to activated CD8+ T cells and demonstrate how an apparent T cell-associated persistent infection can actually be regulated by NK cells...

..We suggest that a similar method for increasing immunogenicity may be applicable to avian influenza vaccines...

..Thus, immunodominance is a function of the host's previous exposure to unrelated pathogens, and this may have an impact on protective immunity and immunopathology...

..Our results support the concept that cross-reactive memory CD8+ T cells activated by EBV contribute to the characteristic lymphoproliferation of IM...

..Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence...

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..Here we discuss examples of altered viral pathogenesis occurring as a consequence of heterologous T cell immunity and propose models for the maintenance of a dynamic pool of memory cells...

..This may contribute to the survival of nondividing peripheral memory T cells, enabling them to efficiently function without being driven into apoptosis...

..Germinal centers were not observed in T-cell-deficient PyV-infected mice, indicating that the germinal center pathway of B-cell differentiation is TD even in the context of a virus infection...

..Our studies suggest that in addition to the reported involvement of TLR9 and TLR3, TLR2 is also involved in innate immune responses to MCMV infection...

..Thus, cross-reactive epitopes can exert pathogenic properties that compromise protective immunity by impairing more protective T cell responses...

..Our findings show that MyD88-dependent signaling pathways in B cells are essential for effectively generating long-term Ab responses and implicate a role for TLR in the formation of long-term humoral immunity...

..Here we will describe the characteristics of CD8 T cells and the dynamics of their response to heterologous viral infections in sequence...

..This study therefore demonstrates CD4 T-cell-mediated heterologous immunity between a bacterium and virus. Further, it poses the question of whether BCG immunization of humans alters resistance to unrelated pathogens...

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..This is in part accounted for by crossreactive memory T cells, which can be employed in immune responses and mediate protective immunity or life-threatening immunopathology...

..These results indicated that immunoproteasomes were more important in antigen presentation than previously thought...

..Inhibition of T cell receptor-stimulated bystander CD8 T cell proliferation during acute viral infections may reflect the reduced ability of vaccines to elicit protective immunity when administered during an acute illness...

..Heterologous immunity thus occurs between many viruses, resulting in altered protective immunity and lung immunopathology, and this is influenced by the specific virus infection sequence...

..We suggest that G2+CD8+ cells represent a cell lineage distinct from bona fide memory T cells, but that they can participate in an acute virus-specific T cell response...

..Together, these findings suggest that TNF expression by naïve T cells is regulated via a gradual licensing process that requires functional maturation in peripheral lymphoid organs...

..Here, we discuss evidence from studies in mice and humans that shows the importance of this phenomenon in determining the outcome of infection...

..Evidence is presented showing that high levels of T cell attrition, as found in young mice, correlate with reduced immunodomination by cross-reactive memory cells...

..Thus, gammadelta T cells can be mediators of innate immunity to viruses, having a significant impact on virus replication early in infection in the presence or absence of the adaptive immune response...

..Apoptotic attrition of bystander T cells may make room for the antigen-specific expansion of T cells during infection and may, in part, account for the loss of T-cell memory that occurs when the host undergoes subsequent infections...

..Recommendations are made for techniques for propagating LCMV to high titers to quantify it by plaque assay and PCR techniques and to preserve its infectivity by appropriate storage...

..These results are consistent with a model for the immune system that accommodates memory T cell populations for multiple pathogens over the course of a lifetime...

..These results indicate that how a host responds to an infectious agent is a function of its history of previous infections and their influence on the memory T cell pool...

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..Our studies demonstrate that, although about half of the TI IgG responses to PyV are independent of CD40-CD40L interactions, these interactions occur in T cell-deficient mice and enhance antiviral TI Ab responses...

..CD8(+) T cells expressing Ly49G2 were selectively expanded by poly I:C and participated in the antigen-specific response to lymphocytic choriomeningitis virus...

..These results may explain why the Cmv-lr locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver...

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..This demonstrates that virus infections do not occur in immunological isolation, and that CD8+ T cell responses are continually being modulated by other infectious agents...

..Inactivated virus or virus-like particles can stimulate IgM production, but factors induced during live virus infection appear to be required to induce the isotype switch that leads to IgG or IgA responses...

..Clinical application of stem cell transplantation protocols based on costimulation blockade and tolerance induction may require patient isolation to facilitate the procedure and to protect recipients...

..Clinical application of transplantation tolerance protocols may require patient isolation to facilitate the procedure and to protect recipients...

..Thus, the participation of pre-existing memory T cells specific to unrelated agents can alter the dynamics of mucosal immunity and disease course in response to a pathogen...

..This finding indicates that clonal exhaustion of CTL does not require IFN-gamma or Fas, even though both molecules influence AICD and the transient immune deficiency seen in the LCMV infection...

..Thus, memory alpha beta T cells can, like gamma delta T cells and NK cells, provide natural immunity to viral infections...

..Antibiotic treatment of mice prevents autoantibody development. Centrosome autoantibodies may provide an aetiological link between infection and human autoimmunity and suggest novel therapeutic strategies in these disorders...

..Last, we show that purified LCMV-specific CD8 T cells rejected skin allografts in SCID mice. These findings therefore implicate a potential role for heterologous immunity in virus-induced allograft rejection...

..These new techniques have shown that functional inactivation and apoptotic elimination of both virus-specific and non-virus-specific T cell populations mold T cell responses to viral infections...

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..These findings suggest that blockade of pathogenic factor actions, in general, may be advantageous to the infected host...

..Collectively, these findings show that chemical inhibitors of host-signaling pathways exploited by viral pathogens may represent potent antiviral therapies...

..Understanding how humoral immunity is maintained will shed light on strategies for the development of long term protective vaccination-induced antibody responses. ..

..The proposed experiments should help elucidate how NK cells respond to stimuli within an infected animal, such that they may effectively contribute to natural immunity...

..abstract_text> ..

..By manipulating this highly defined LCMV model in vivo, fundamental concepts concerning immunoregulation and immune deficiencies applicable to human viral infections should be obtained. ..

..Understanding the implications of this "heterologous immunity" in normal and aged hosts should enhance our knowledge of viral pathogenesis and contribute to the design of better vaccines. ..

..Understanding how humoral immunity is maintained will shed light on strategies for the development of long term protective vaccination-induced antibody responses. ..

..abstract_text> ..

..SPECIFIC AIM #4. To determine the basis for the deficiency of virus-specific T cells in the homeostatic reconstitution of lymphopenic environments. ..

..This Immunology Training Grant has been an integral part of our program for the past 12 years, and we are requesting another 5 years of support. ..

..This work should clarify how these effector systems act and interact to rid the host of infectious agents and tumors. ..

..to do a molecular analysis of NK- sensitive and NK-resistant variants of PV, in order to determine which viral gene product confers the phenotype of NK-sensitivity. ..

..This work should help define the parameters of natural immunity to virus infections and will determine whether natural effector cells can be used to control infections therapeutically...