John Harty

..The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material...

..In addition, Listeria-specific CD8 T cells lyse Listeria-infected hepatocyte-like cells in vitro. Thus, Listeria-infected hepatocytes can be recognized by CD8 T cells in vivo and in vitro...

..Here, we dissect the input signals that shape the characteristics of the memory CD8+ T-cell response and discuss how manipulation of these signals has the potential to reshape CD8+ T-cell memory and improve the efficacy of vaccination...

..Finally, recent studies of human CD8(+) T cells reveal the potential for novel effector mechanisms in resistance to infection...

....

..These results, together with advances in our understanding of nonclassical MHC class I presentation, reveal the impact of pathogen biology on host immunity to infection...

..Our findings argue against such a possibility and rather suggest that GABPbeta1S has a critical role in maintaining the transcriptional activity of the GABPalpha/beta complex...

..Thus, T cells are not able to undergo rapid ON/OFF/ON cytokine cycling in vitro in response to Ag...

....

..These results indicate that expression of IL-7Ralpha alone does not support increased survival of effector Ag-specific CD4 or CD8 T cells into the memory phase following bacterial infection...

....

..In recent years it has been determined that CD4 T cells play a vital role in the survival and functional responsiveness of memory CD8 T cells. However, the mechanism(s) of this interaction are still unclear...

..Thus, constitutive activation of the canonical Wnt pathway favors memory CD8 T cell formation during initial immunization, resulting in enhanced immunity upon second encounter with the same pathogen...

..This concept has direct relevance to development of vaccines in outbred humans...

....

..Using this method, we directly identify differences in IL-2 production capacity by CD62L(hi)- and CD62L(lo)-expressing antigen-specific memory CD8 T cell populations...

..These data may suggest new strategies for manipulating vaccine efficacy in the quest to protect against pathogenic microbes...

..Our results confirm the necessity to use low numbers of naïve precursors to mimic endogenous immune responses but show at the same time that memory CD8 T cell function in adoptive transfers is independent of input numbers...

..Our results suggest that CD62L is not a deterministic marker of central memory T cell differentiation, thus providing new insight into the process of memory CD8 T cell generation...

..Therefore, our study has important implications for the design of prime-boost regimens that aim to generate protective CD8(+) T-cell-mediated immunity...

..The possibility that early events after infection regulate major features of Ag-specific CD8(+) T-cell homeostasis will be discussed here...

..Thus, contraction is controlled by early inflammation but is not essential for the generation of protective memory CD8(+) T cells after infection...

..This protection was enhanced by diversifying the memory CD8(+) T cell compartment, even in the absence of a large increase in Ag-specific CD8(+) memory T cells...

..Herein, we discuss our current understanding of how inflammation shapes not only the quantity and quality of memory T cells, but also the rate at which functional memory T-cell populations develop...

..Our studies thus identify TCF-1 as a critical player in a transcriptional program that regulates memory CD8 differentiation and longevity...

....

..monocytogenes replication. Thus, the level of antivector immunity impacts the control of infection and efficiency of priming responses against new antigens introduced with the same vector...

....

..These results reveal the complex regulation of memory CD8(+) T cell differentiation and identify potential new molecular targets to dissect the function of memory cells generated by repeated antigen stimulation...

..These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines...

..Our studies also show that the effector pathways that memory CD8 T cells use to eliminate liver stage infection are, in part, Plasmodium species specific...

..Thus, identification of novel CD4 and CD8 T cell epitopes for MHV-1 permitted high-resolution analyses of pulmonary T cell responses in a mouse model of SARS...

..Thus, accelerated CD8 T-cell memory after in vivo cross-priming in the absence of adjuvant is generalizable and can be exploited to generate protective immunity rapidly...

..Furthermore, the extremely large threshold in memory CD8 T cell frequencies required for long-term protection in mice may have important implications for development of effective malaria vaccines...

..monocytogenes infection...

..Therefore, initial protection by a CD8 T cell-targeted liver stage subunit vaccine allows the generation of enhanced sterilizing immune responses from repeated exposure to Plasmodium parasites...

..These data suggest that a default pathway of memory CD8 T cell differentiation is deflected toward sustained effector commitment by encounter with inflammatory cytokines during Ag-driven proliferation...

..Overall, our findings highlight the role of the host immune response in contributing to the pathogenesis of coronavirus-induced respiratory disease...

..The generation of antigen-specific CD8 T cells, therefore, is a potential approach in the design of vaccines, especially for those pathogens in which the humoral response is insufficient to protect the host...

..Recent evidence demonstrates that anti-microbial effector molecules such as perforin and IFN-gamma regulate specific aspects of CD8(+) T cell homeostasis by mechanisms that may be dependent or independent of pathogen clearance...

..Thus, perforin was essential for resistance to secondary LCMV infection, and, in the absence of perforin, vaccination resulted in lethal disease mediated by dysregulated CD8(+) T cell expansion and cytokine production...

..Thus, increasing the number of memory CD8(+) T cells can overcome diminished per-cell protective immunity in the absence of perforin...

..Thus, protective immunity by H2-M3-restricted T cells is limited to primary infection, indicating that memory MHC class Ia-restricted T cells prevent nonessential immune responses during secondary infection...

....

..These findings suggest a differential requirement for spMHC signals for maintenance of CD8 T cell function and homeostatic proliferation...

..Thus, primary and secondary memory CD8 T cells are functionally distinct, and the number of encounters with antigen influences memory CD8 T cell function...

....

..Finally, we discuss experimental approaches to manipulate and accelerate generation of CD8+ T cells with memory characteristics, and how these systems can inform both basic and applied immunology...

..Conventional analyses of memory CD8 T cell populations early after infection and possibly in the presence of low levels of Ag (as during chronic infections) may exclude significant numbers of the responding CD8 T cell population...

....

..These data strongly suggest that modeling the endogenous T cell response with TCR-tg cells will require every effort to approximate the endogenous precursor frequency...

..From these data we conclude that IFN-gamma regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection...

..In this article, we discuss recent advances in understanding how antigenic stimulation influences expression of various trafficking receptors and ligands, and how this determines the tissue localization of CD8 T cells...

..In addition, cross-presentation of bacterial Ags from neutrophils may explain how CD8(+) T cell responses are generated against Ags from extracellular bacterial pathogens...

..These results demonstrate a direct relationship between the course of infection and Ag display and that the timing of these events is important in shaping the T-cell response to infection...

..We conclude that the generation of protective immunity by LLO-deficient strains of LM does in fact occur and that this highly attenuated LM strain may be a useful platform for vaccine delivery...

..Thus, major features of antigen-specific CD8(+) T cell homeostasis, including the contraction phase of an immune response, may be programmed early after infection...

..Being able to influence the memory T-cell make-up in a rational manner may allow us to develop more efficacious vaccines...

..In addition, these findings demonstrate that reactivity to peptides is preferred over the reactivity to MHC during the formation of the TCR repertoire...

..Our data suggest that T(EM) cells are important as a first line of defense against fast-replicating pathogens such as murine Plasmodium and demonstrate the potential of replication-defective SAd as future malaria vaccines for humans...

..Aim-3. Investigate the mechanisms responsible for prolonged contraction of CD8+ T cells during the secondary response to infection. ..

..Aim 3. Determine if accelerated memory and prime-boost after DC immunization improves immunotherapy against established tumors and protection against malaria and leishmaniasis. ..

..Specific Aim 2. Determine if IFN-gamma regulates T cell contraction through p53 and/or IL-18 signaling. Specific Aim 3. Determine the requirements for IFN-alpha-beta and IFN-gamma signaling in regulating CDS T cell expansion. ..

..Aim 3. Analyze CD8+ T cell and pathogen parameters that determine the outcome of LCMV infection in vaccinated PKO mice. Aim 4. Determine if vaccination-associated mortality extends to other immunodeficiencies or pathogens. ..

..Determine if IFN-gamma regulates T cell contraction through p53 and/or IL-18 signaling. Specific Aim 3. Determine the requirements for IFN-alpha-beta and IFN-gamma signaling in regulating CDS T cell expansion. ..

..Aim 3. Determine if accelerated memory and prime-boost after DC immunization improves immunotherapy against established tumors and protection against malaria and leishmaniasis. ..

....

..The results of these studies will provide important information for vaccine design strategies and emerging approaches to the immunotherapy of human infectious diseases. ..

..Such basic information will impact evolving strategies for rational vaccine design, addressing the utility of the various antigen presentation pathways for vaccine delivery and for providing targets for protective immunity. ..

..Addressing this knowledge gap would aid in the rational design of malaria vaccines and is the goal of this proposal. ..