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David L Woodland

Publications and source records attributed to David L Woodland.

At least 19 recordsLinked to original sources
PubMed2007

Priming with cold-adapted influenza A does not prevent infection but elicits long-lived protection against supralethal challenge with heterosubtypic virus.

We show in this study several novel features of T cell-based heterosubtypic immunity against the influenza A virus in mice. First, T cell-mediated heterosubtypic protection against lethal challenge can be generated by a very low priming dose. Second, it becomes effective within 5-6 days. Third, it provides protection against a very high dose challenge for >70 days. Also novel is the finding that strong, long-lasting, heterosubtypic protection can be elicited by priming with attenuated cold-adapted strains. We demonstrate that priming does not prevent infection of the lungs following challenge, but leads to earlier clearance of the virus and 100% survival after otherwise lethal challenge. Protection is dependent on CD8 T cells, and we show that CD4 and CD8 T cells reactive to conserved epitopes of the core proteins of the challenge virus are present after priming. Our results suggest that intranasal vaccination with cold-adapted, attenuated live virus has the potential to provide effective emergency protection against emerging influenza strains for several months.

Adaptation, Biological↗
PubMed2007

Aging and CD8+ T cell immunity to respiratory virus infections.

The capacity of the immune system to mediate effective immune responses to pathogens declines with age. In the case of immune responses to newly encountered antigens, several studies have demonstrated that this decline reflects both a loss of naïve T cells and changes in the repertoire and function of these cells over time. However, comparatively little is known about the impact of age on established memory T cells pools. Here we discuss age-related changes in memory CD8(+) T cell pools elicited by influenza and parainfluenza viruses and the impact of these changes on immunity in general.

Aging↗
PubMed2006

Aryl hydrocarbon receptor activation impairs the priming but not the recall of influenza virus-specific CD8+ T cells in the lung.

The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR(+/+) recipients, and the generation of CD45.2AhR(-/-)-->CD45.1AhR(+/+) chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.

Animals↗
PubMed2006

Immunity and age: living in the past?

Increasing age is associated with a decreasing ability to mediate effective immune responses to newly encountered antigens. It is generally believed that this reflects the age-associated decline in the number, repertoire and function of available naive T cells. Here, we propose that naive T cells become increasingly irrelevant to the immune system, and that responses to newly encountered antigens are progressively dominated by cross-reactive memory T cells as the individual ages. In addition, we propose that the majority, if not all, of the response to newly encountered antigens in the elderly is mediated by cross-reactive memory T cells. This predicts highly stochastic responses to new infections that should vary between individuals, and has important implications for vaccination strategies in the elderly.

Aged↗
PubMed2006

Memory T cell recruitment to the lung airways.

Memory T cells play an important role in the resolution of secondary respiratory virus infections through the production of anti-viral cytokines and the lysis of infected cells. Within the lung airways, memory T cells form an initial line of defense against secondary virus challenge by limiting early viral replication at the site of infection. Recent studies have addressed the generation and maintenance of airway memory T cells and their relationship with memory T cells in the secondary lymphoid organs. These advances have demonstrated that different memory subsets contribute to the maintenance of the airway memory T cell population and have identified molecules that influence trafficking to the lung tissue and the lung airways.

Animals↗
PubMed2006

Memory T cell populations in the lung airways are maintained by continual recruitment.

Effector memory T cell populations in the periphery play a key role in cellular immune responses to secondary infections. However, it is unclear how these populations are maintained under steady-state conditions in nonlymphoid peripheral sites, such as the lung airways. In this study, we show that LFA-1 expression is selectively down-regulated following entry of memory T cells into the lung airways. Using Sendai virus as a mouse model of respiratory virus infection, we use LFA-1 expression levels to demonstrate that effector memory T cell populations in the lung airways are maintained by continual recruitment of new cells from the circulation. The rate of memory cell recruitment is surprisingly rapid, resulting in replacement of 90% of the population every 10 days, and is maintained for well over 1 year following viral clearance. These data indicate that peripheral T cell memory is dynamic and depends on a systemic source of T cells.

Adoptive Transfer↗
PubMed2006

T-cell memory and recall responses to respiratory virus infections.

The respiratory tract is characterized by its large surface area and the close association of an extensive vasculature with the external environment. As such, the respiratory tract is a major portal of entry for many pathogens. The immune system is able to effectively control most pulmonary pathogens and establish immunological memory that is capable of mediating an accelerated and enhanced recall response to secondary pathogen challenge. A key component of the recall response in the lung involves the rapid response of antigen-specific memory CD8+ T cells. Recent studies have shown that memory CD8+ T cells are extremely heterogeneous in terms of phenotype, function, anatomical distribution, and longevity. However, we have little understanding of how the different subsets of memory cells actually contribute to the recall response, especially with respect to peripheral or mucosal sites, such as the lung. Since immunological memory is the cornerstone of vaccination, it is essential that we understand how different memory CD8+ T-cell subsets are initially generated, maintained over time, and contribute to recall responses. This review focuses on memory T cells that mediate recall responses to influenza and parainfluenza virus infections in the lung.

Animals↗
PubMed2005

Tissue-resident memory CD8+ T cells can be deleted by soluble, but not cross-presented antigen.

Under noninflammatory conditions, both naive and central memory CD8 T cells can be eliminated in the periphery with either soluble peptide or cross-presented Ag. Here, we assess the tolerance susceptibility of tissue-resident memory CD8 T cells in mice to these two forms of tolerogen. Soluble peptide specifically eliminated the majority of memory CD8 cells present in both lymphoid and extralymphoid tissues including lung and liver, but was unable to reduce the number present in the CNS. In contrast, systemic cross-presentation of Ag by dendritic cells resulted in successful elimination of memory cells only from the spleen, with no significant reduction in the numbers of tissue-resident memory cells in the lung. The fact that tissue-resident memory cells were unable to access cross-presented Ag suggests that either the memory cells in the lung do not freely circulate out of the tissue, or that they circulate through a region in the spleen devoid of cross-presented Ag. Thus, although tissue-resident memory cells are highly susceptible to tolerance induction, both the form of tolerogen and location of the T cells can determine their accessibility to tolerogen and the degree to which they are successfully deleted from specific tissues.

Animals↗
PubMed2005

Infection of dendritic cells by a gamma2-herpesvirus induces functional modulation.

The murine gamma-herpesvirus-68 (gammaHV68) establishes viral latency in dendritic cells (DCs). In the present study, we examined the specific consequences of DC infection by gammaHV68, both in vivo and in vitro. Ex vivo analysis of infected mice showed that the virus colonizes respiratory DCs very early after infection and that all subsets of splenic DCs analyzed are viral targets. We have developed and characterized an in vitro model of gammaHV68 infection of DCs. Using this model, we demonstrated that viral infection neither induces full DC maturation nor interferes with exogenous activation, which is assessed by cell surface phenotypic changes. However, whereas gammaHV68 infection alone failed to elicit cytokine secretion, IL-10 secretion of exogenously activated DCs was enhanced. Furthermore, gammaHV68-infected DCs efficiently stimulated virus-specific T cell hybridomas but failed to induce alloreactive stimulation of normal T cells. These data indicate that viral infection doesn't interfere with Ag processing and presentation but does interfere with the ability of DCs to activate T cells. The inhibition of T cell activation was partially reversed by blocking IL-10. Analysis of infected mice shows elevated levels of IL-10 expression in DCs and that lack of endogenous IL-10 is associated with decreased gammaHV68 long-term latency. Taken together, these observations indicate that gamma2-herpesvirus infection of DCs is a mechanism of viral immune evasion, partially mediated by IL-10.

Animals↗
PubMed2005

Production of calcium-mobilizing metabolites by a novel member of the ADP-ribosyl cyclase family expressed in Schistosoma mansoni.

ADP-ribosyl cyclases are structurally conserved enzymes that are best known for catalyzing the production of the calcium-mobilizing metabolite, cyclic adenosine diphosphate ribose (cADPR), from nicotinamide adenine dinucleotide (NAD(+)). However, these enzymes also produce adenosine diphosphate ribose (ADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP(+)), both of which have been shown to modulate calcium mobilization in vitro. We have now characterized a new member of the cyclase family from Schistosoma mansoni, a member of the Platyhelminthes phylum. We show that the novel NAD(P)(+) catabolizing enzyme (NACE) expressed by schistosomes is structurally most closely related to the cyclases cloned from Aplysia but also shows significant homology with the mammalian cyclases, CD38 and CD157. NACE expression is developmentally regulated in schistosomes, and the GPI-anchored protein is localized to the outer tegument of the adult schistosome. Importantly, NACE, like all members of the cyclase family, is a multifunctional enzyme and catalyzes NAD(+) glycohydrolase and base-exchange reactions to produce ADPR and NAADP(+). However, despite being competent to generate a cyclic product from NGD(+), a nonphysiologic surrogate substrate, NACE is so far the only enzyme in the cyclase family that is unable to produce significant amounts of cADPR (<0.02% of reaction products) using NAD(+) as the substrate. This suggests that the other calcium-mobilizing metabolites produced by NACE may be more important for calcium signaling in schistosomes. Alternatively, the function of NACE may be to catabolize extracellular NAD(+) to prevent its use by host enzymes that utilize this source of NAD(+) to facilitate immune responses.

ADP-ribosyl Cyclase↗
PubMed2005

Identification of protective and non-protective T cell epitopes in influenza.

Understanding the immune response to different CD8 T cell epitopes is important for the development of vaccines designed to promote protective cellular immunity. Recently, we have shown that vaccination with the PA(224-233)/D(b) epitope of influenza virus was poorly protective in terms of viral clearance. To determine if other influenza virus epitopes behave in this manner, we analyzed the ability of three newly identified CD8 T cell epitopes and three previously defined epitopes to provide protection following vaccination and viral challenge. All six of the peptide-based vaccinations resulted in significantly increased numbers of epitope-specific CD8 T cells in the spleen. Interestingly, we found that vaccination with three peptides (HA(332-340), M1(128-135), or PA(224-233)) resulted in delayed viral clearance following infection. These findings indicate that some epitopes have a detrimental impact on viral clearance and have important implications for the development of vaccination strategies designed to provide protection against subsequent influenza virus challenge.

Animals↗
PubMed2005

Uneven distribution of MHC class II epitopes within the influenza virus.

The identification of T cell epitopes is crucial for the understanding of the host immune response during infection. While much is known about the MHC class I-restricted response following influenza virus infection of C57BL/6 mice, with over 16 CD8 epitopes identified to date, less is known about the MHC class II-restricted response. Currently, only a few I-A(b)-restricted T helper epitopes have been identified. Therefore, several important questions remain about how many class II epitopes exist in this system and whether these epitopes are evenly distributed within the most abundant viral proteins. In order to address these questions, we analyzed the repertoire of epitopes that drive the CD4+ approximately 20-30 epitopes drive the CD4 T cell response and that the majority of these peptides are derived from the NP and HA proteins. We were also able to demonstrate that vaccination with one of the newly identified epitopes, HA(211-225)/A(b), resulted in increased epitope-specific T cell numbers and a significant reduction in viral titers following influenza virus challenge.

Animals↗
PubMed2005

Differential contributions of central and effector memory T cells to recall responses.

Although the absolute number of memory CD8+ T cells established in the spleen following antigen encounter remains stable for many years, the relative capacity of these cells to mediate recall responses is not known. Here we used a dual adoptive transfer approach to demonstrate a progressive increase in the quality of memory T cell pools in terms of their ability to proliferate and accumulate at effector sites in response to secondary pathogen challenge. This temporal increase in efficacy occurred in CD62L lo (effector memory) and CD62L hi (central memory) subpopulations, but was most prominent in the CD62L hi subpopulation. These data indicate that the contribution of effector memory and central memory T cells to the recall response changes substantially over time.

Adoptive Transfer↗
PubMed2005

The functional heterogeneity of type 1 effector T cells in response to infection is related to the potential for IFN-gamma production.

The expression of IFN-gamma is a hallmark of Th1 cells and CD8(+) effector T cells and is the signature cytokine of type 1 responses. However, it is not known whether T cells are homogeneous in their capacity to produce IFN-gamma, whether this potential varies between tissues, and how it relates to the production of other effector molecules. In the present study we used bicistronic IFN-gamma-enhanced yellow fluorescent protein (IFN-gamma-eYFP) reporter mice (Yeti) and MHC class I tetramers to directly quantify IFN-gamma expression at the single cell level. The eYFP fluorescence of Th1 cells and CD8(+) effector T cells was broadly heterogeneous even before cell division and correlated with both the abundance of IFN-gamma transcripts and the secretion of IFN-gamma upon stimulation. CD4(+) and CD8(+) T cells of influenza-infected mice revealed a similarly heterogeneous IFN-gamma expression, and eYFP(high) cells were only found in the infected lung. Ag-specific T cells were in all examined tissues eYFP(+), but also heterogeneous in their reporter fluorescence, and eYFP(high) cells were also restricted to the infected lung. A similar heterogeneity was observed in Toxoplasma gondii-infected animals, but eYFP(high) cells were restricted to different tissues. Highly eYFP fluorescent cells produced elevated levels of proinflammatory cytokines and chemokines in addition to IFN-gamma, suggesting their coregulated expression as a functional unit in highly differentiated effector T cells.

Animals↗
PubMed2005

Early establishment of gamma-herpesvirus latency: implications for immune control.

The human gamma-herpesviruses, EBV and Kaposi's sarcoma-associated herpesvirus, infect >90% of the population worldwide, and latent infection is associated with numerous malignancies. Rational vaccination and therapeutic strategies require an understanding of virus-host interactions during the initial asymptomatic infection. Primary EBV infection is associated with virus replication at epithelial sites and entry into the circulating B lymphocyte pool. The virus exploits the life cycle of the B cell and latency is maintained long term in resting memory B cells. In this study, using a murine gamma-herpesvirus model, we demonstrate an early dominance of latent virus at the site of infection, with lung B cells harboring virus almost immediately after infection. These data reinforce the central role of the B cell not only in the later phase of infection, but early in the initial infection. Early inhibition of lytic replication does not impact the progression of the latent infection, and latency is established in lymphoid tissues following infection with a replication-deficient mutant virus. These data demonstrate that lytic viral replication is not a requirement for gamma-herpesvirus latency in vivo and suggest that viral latency can be disseminated by cellular proliferation. These observations emphasize that prophylactic vaccination strategies must target latent gamma-herpesvirus at the site of infection.

Animals↗
PubMed2005

Vaccination with an acidic polymerase epitope of influenza virus elicits a potent antiviral T cell response but delayed clearance of an influenza virus challenge.

The mechanisms underlying epitope selection and the potential impact of immunodominance hierarchies on peptide-based vaccines are not well understood. Recently, we have shown that two immunodominant MHC class I-restricted epitopes, NP(366-374)/D(b) (nucleoprotein (NP)) and PA(224-233)/D(b) (acidic polymerase (PA)), which drive the CD8(+) T cell response to influenza virus infection in C57BL/6 mice, are differentially expressed on infected cells. Whereas NP appears to be strongly expressed on all infected cells, PA appears to be strongly expressed on dendritic cells but only weakly expressed on nondendritic cells. Thus, the immune response to influenza virus may involve T cells specific for epitopes, such as PA, that are poorly expressed at the site of infection. To examine the consequences of differential Ag presentation on peptide vaccination, we compared the kinetics of the T cell response and influenza virus clearance in mice vaccinated with the NP or PA peptide. Vaccination with either the NP or PA peptide resulted in accelerated and enhanced Ag-specific T cell responses at the site of infection following influenza virus challenge. These T cells were fully functional in terms of their ability to produce IFN-gamma and TNF-alpha and to mediate cytolytic activity. Despite this enhancement of the Ag-specific T cell response, PA vaccination had a detrimental effect on the clearance of influenza virus compared with unvaccinated or NP-vaccinated mice. These data suggest that differential Ag presentation impacts the efficacy of T cell responses to specific epitopes and that this needs to be considered for the development of peptide-based vaccination strategies.

Adoptive Transfer↗
PubMed2005

Immunity: it's in our bones.

Accumulating data suggest that the bone marrow is a reservoir for memory CD8+ T cells. In this issue of Immunity, show that bone marrow CD8+ T cells are predominantly CCR7+/CD62L+ "central memory" cells and describe specific signals that mediate their constitutive recruitment from the blood.

Animals↗