Kevin L Legge

University of Iowa, Iowa City, Iowa, United States

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Publications (63)355.14 Total impact

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    ABSTRACT: Importance: IAV continues to be a global health burden that infects 5-20% of the global population annual. Continued investigation into the mechanisms that mediate protective immune responses against IAV is important to improving current vaccination and antiviral strategies antagonistic towards IAV. Our findings presented in this manuscript demonstrate a key requirement for pDC promotion of effector CD8 T cell survival: that rather than utilize cross-presentation, pDC must be infected and utilize the endogenous pathway for presentation of antigens to CD8 T cells during in vivo IAV infections. This suggests that targeting presentation via the endogenous pathway in pDC could be important for the development of unique antiviral cellular therapies.
    No preview · Article · Dec 2015 · Journal of Virology
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    ABSTRACT: The extent to which obesity compromises the differentiation and maintenance of protective memory CD8 T cell responses and renders obese individuals susceptible to infection remains unknown. In this study, we show that diet-induced obesity did not impact the maintenance of pre-existing memory CD8 T cells, including acquisition of a long-term memory phenotype (i.e., CD27(hi), CD62L(hi), KLRG1(lo)) and function (i.e., cytokine production, secondary expansion, and memory CD8 T cell-mediated protection). Additionally, obesity did not influence the differentiation and maintenance of newly evoked memory CD8 T cell responses in inbred and outbred hosts generated in response to different types of systemic (LCMV, L. monocytogenes) and/or localized (influenza virus) infections. Interestingly, the rate of naive-to-memory CD8 T cell differentiation after a peptide-coated dendritic cell immunization was similar in lean and obese hosts, suggesting that obesity-associated inflammation, unlike pathogen- or adjuvant-induced inflammation, did not influence the development of endogenous memory CD8 T cell responses. Therefore, our studies reveal that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either primed before or after obesity is established, a surprising notion with important implications for future studies aiming to elucidate the role obesity plays in host susceptibility to infections.
    No preview · Article · Nov 2014 · The Journal of Immunology
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    ABSTRACT: The potential epidemiological human pandemic resulting from highly pathogenic avian influenza (HPAI) H5N1 has been studied extensively since the identification of the virus in the Guangdong province of China. The majority of research has focused on the unique and severe histopathological lesions induced by the virus. The severe pathological presentation of these infections has also prompted interest in identifying preventive and therapeutic approaches against HPAI. The potential severity of a HPAI pandemic and the efforts to identify effective intervention strategies have led to many novel discoveries in vaccine and antiviral development that are critically examined in this review.
    No preview · Article · Sep 2014 · Journal of Biomedical Nanotechnology
  • Emily A. Hemann · Jodi L. McGill · Kevin L. Legge
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    ABSTRACT: Background It is well established that chronic ethanol (EtOH) consumption is associated with increased incidence and disease severity of respiratory infections. Our recent work demonstrates this increase in disease severity to influenza A virus (IAV) infections is due, in part, to a failure to mount a robust IAV-specific CD8 T cell response along with a specific impairment in the ability of these T cells to produce interferon γ (IFNγ). However, the full extent of the lesion in the effector CD8 T cell compartment during chronic EtOH consumption remains unknown.Methods Utilizing the Meadows–Cook murine model of chronic alcohol consumption, mice received EtOH in their drinking water for 8 or 12 weeks. Mice were challenged intranasally with IAV, and the activation and effector functions of IAV-specific CD8 T cells were determined in both the lung-draining lymph nodes (dLN) and lungs.ResultsOur results confirm the defect in IFNγ production; however, the ability of IAV-specific T cells to produce tumor necrosis factor α (TNFα) and interleukin-2 (IL-2) in EtOH-consuming mice remains unaltered. In contrast, EtOH consumption significantly reduces the ability of CD8 T cells to degranulate and kill IAV-specific targets. Finally, our findings suggest the lesion begins during the initial activation of CD8 T cells, as we observe early defects in proliferation in the dLN of IAV-infected, EtOH-consuming mice.Conclusions These findings highlight the previously unrecognized depth of the lesion in the IAV-specific CD8 T cell response during chronic EtOH consumption. Given the important role CD8 T cell immunity plays in control of IAV, these findings may aid in the development of vaccination and/or therapeutic strategies to reverse these defects in the CD8 T cell response and reduce serious disease outcomes associated with IAV infections in alcoholics.
    No preview · Article · Aug 2014 · Alcoholism Clinical and Experimental Research
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    ABSTRACT: Influenza A virus (IAV) infection represents a significant global public health burden in addition to its potential as a pandemic killer. Accordingly, the immune response within the respiratory tract and associated lymphoid tissues has been a focus of study for decades. Murine model systems have led to a relatively clear understanding that while innate and T-cell responses are essential for clearance of an initial infection, high affinity neutralizing antibodies (Abs) generated by long-lived Ab forming cells and memory B cells are critical for protection from reinfection and are the goal of classic vaccination strategies. Indeed, the local and systemic IAV-specific Ab response after primary pulmonary infection has been well studied in mice. However, the highly organized microenvironments responsible for producing long-lived, high affinity responses, namely germinal center (GC) reactions, have been less well studied. Recently, work from our laboratory and others has provided new insights into the induction and character of IAV-specific GC responses in the secondary lymphoid organs and the lung. Of interest, these studies have demonstrated IAV reactive GCs to persist for extended periods in both draining lymph nodes and lung tissue. Herein, the primary adaptive response to IAV is reviewed with an emphasis on GC B-cell responses. In addition, data are shown demonstrating the persistence of GCs in the respiratory tract after IAV infection, and key factors that drive their maintenance.
    No preview · Article · May 2014 · Immunologic Research
  • Emily A Hemann · Kevin L Legge
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    ABSTRACT: It is well accepted that T cell responses are integral in providing protection during pathogenic infections. In numerous tissues, T cell responses are generated to combat infection. Typically, these T cell responses are primed in draining lymph nodes (LN) by dendritic cells (DC) that have migrated from the infected tissue. Previously, it was thought that after the initial encounter between DC and T cells in the LN, the T cells underwent a programmed response. However, it has become increasingly clear that direct interactions between DCs and T cells in infected, peripheral tissues can modulate the activation, effector function, tissue residence, and memory responses of these T cells. This review will highlight the contribution of local, direct DC: T cell interactions to the regulation of T cell responses in various tissues during inflammation and infection .
    No preview · Article · May 2014 · Immunologic Research
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    ABSTRACT: Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes (LNs), and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining LNs postinfection with a lethal A/HK/483/97 or nonlethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not nonlethal H5N1, virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8(+) T cells via a Fas-FasL-mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining LNs of lethal H5N1 virus-infected mice, and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining LNs. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs.
    Preview · Article · May 2014 · The Journal of Immunology
  • Kevin L. Legge · Thomas J. Waldschmidt
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    ABSTRACT: It is well established that alcoholics have an increased incidence of respiratory diseases. Further, chronic alcoholism predisposes for more severe disease following respiratory infections. While many studies have detailed the increase in disease severity during respiratory infections in alcoholics, much less is understood about the underlying mechanisms through which chronic alcohol consumption mediates this increase in disease severity or how alcohol alters pulmonary adaptive immune responses. It is well accepted that chronic alcohol ingestion is immunosuppressive and exerts inhibitory effects on adaptive immunity. However, these studies have largely focused on examining the immunosuppression of cell-mediated immunity in the spleen, skin, and liver. Importantly, for many pathogens the type of immune response generated in the respiratory and intestinal mucosa is distinct from that generated following intravenous, intraperitoneal, or subcutaneous exposures. Therefore, the type and extent of lesions that exist in the respiratory adaptive immune system of alcoholics and the consequences of these lesions, particularly during infections, remain in question. This chapter highlights and discusses the field’s current knowledge on chronic alcohol-induced lesions within the pulmonary dendritic cell and T cell compartments and the relationship of these lesions to increased respiratory disease.
    No preview · Chapter · Jan 2014

  • No preview · Article · Nov 2013 · Alcohol
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    Emily A Hemann · Sang-Moo Kang · Kevin L Legge
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    ABSTRACT: The development of influenza A virus (IAV) vaccines capable of inducing cytotoxic CD8 T cell responses could potentially provide superior, long-term protection against multiple, heterologous strains of IAV. Although prior studies demonstrated the effectiveness of baculovirus-derived virus-like particle (VLP) vaccination in generating Ab-mediated protection, the role that CD8 T cell immunity plays in overall VLP-mediated protection is less-well understood. In this article, we demonstrate that intranasal vaccination of mice with a VLP containing the hemagglutinin and matrix 1 proteins of IAV/PR/8/34 leads to a significant increase in hemagglutinin 533-specific CD8 T cells in the lungs and protection following subsequent homologous challenge with IAV. VLP-mediated protection was significantly reduced by CD8 T cell depletion, indicating a critical role for CD8 T cells in protective immunity. Importantly, our results show that VLP vaccine-induced CD8 T cell-mediated protection is not limited to homologous IAV strains. VLP vaccination leads to an increase in protection following heterosubtypic challenge with a strain of IAV that avoids vaccine-induced neutralizing Abs but contains conserved, immunodominant CD8 T cell epitopes. Overall, our results demonstrate the ability of influenza protein-containing VLPs to prime IAV-specific CD8 T cell responses that contribute to protection from homo- and heterosubtypic IAV infections. These results further suggest that vaccination strategies focused on the development of cross-protective CD8 T cell responses may contribute to the development of "universal" IAV vaccines.
    Full-text · Article · Jul 2013 · The Journal of Immunology
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    ABSTRACT: Rationale: Inflammation and autonomic dysfunction contribute to the pathophysiology of hypertension. Cholinergic stimulation suppresses innate immune responses. Angiotensin II (Ang II) induces hypertension and is associated with proinflammatory immune responses. Objective: Our goal was to define the innate immune response in a model of genetic hypertension and the influences of cholinergic stimulation and Ang II. Methods and results: Studies were conducted on 4- to 5-week-old prehypertensive spontaneously hypertensive rats (SHRs) and age-matched normotensive control, Wistar Kyoto (WKY) rats. Isolated splenocytes were preexposed to nicotine or Ang II before Toll-like receptor (TLR) activation. Culture supernatants were tested for cytokines (tumor necrosis factor-α, interleukin [IL]-10, and IL-6). TLR-mediated cytokine responses were most pronounced with TLR7/8 and TLR9 activation and similar between WKY rats and SHRs. Nicotine and Ang II enhanced this TLR-mediated IL-6 response in prehypertensive SHR splenocytes. In contrast, nicotine suppressed the TLR-mediated IL-6 response in WKY rats, whereas Ang II had no effect. In vivo, nicotine enhanced plasma levels of TLR7/8-mediated IL-6 and IL-1β responses in prehypertensive SHRs but suppressed these responses in WKY rats. Flow cytometry revealed an increase in a CD161+ innate immune cell population, which was enhanced by nicotine in the prehypertensive SHR spleen but not in WKY. Conclusions: There is a pronounced anti-inflammatory nicotinic/cholinergic modulation of the innate immune system in WKY rats, which is reversed in prehypertensive SHRs. The results support the novel concept that neurohormonal regulation of the innate immune system plays a role in the pathogenesis of genetic hypertension and provide putative molecular targets for treatment of hypertension.
    No preview · Article · Aug 2012 · Circulation Research
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    ABSTRACT: Protection from influenza A virus (IAV) challenge requires switched, high affinity Abs derived from long-lived memory B cells and plasma cells. These B cell subsets are generated in germinal centers (GCs), hallmark structures of T helper cell-driven B cell immunity. A full understanding of the GC reaction after respiratory IAV infection is lacking, as is the characterization of T follicular helper (T(FH)) cells that support GCs. Here, GC B cell and T(FH) cell responses were studied in mice following pulmonary challenge with IAV. Marked GC reactions were induced in draining lymph nodes (dLNs), lung, spleen and nasal-associated lymphoid tissue (NALT), although the magnitude and kinetics of the response was site-specific. Examination of switching within GCs demonstrated IgG2(+) cells to compose the largest fraction in dLNs, lung and spleen. IgA(+) GC B cells were infrequent in these sites, but composed a significant subset of the switched GC population in NALT. Further experiments demonstrated splenectomized mice to withstand a lethal recall challenge, suggesting the spleen to be unnecessary for long-term protection in spite of strong GC responses in this organ. Final studies showed that T(FH) cell numbers were highest in dLNs and spleen, and peaked in all sites prior to the height of the GC reaction. T(FH) cells purified from dLNs generated IL-21 and IFNγ upon activation, although CD4(+)CXCR5(-) T effector cells produced higher levels of all cytokines. Collectively, these findings reveal respiratory IAV infection to induce strong T helper cell-driven B cell responses in various organs, with each site displaying unique attributes.
    Preview · Article · Jul 2012 · PLoS ONE
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    Dataset: Figure S2
    Alexander W. Boyden · Kevin L. Legge · Thomas J. Waldschmidt
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    ABSTRACT: dLNs contain the highest percent of switched GC B cells following IAV infection. Animals were infected i.n. with a 0.1LD50 dose of IAV on day 0. dLNs, lung, and spleen were harvested on days 8–30 post-infection and stained with PNA, anti-B220 mAb and anti-IgM mAb. Bar graphs represent the percent of switched (IgM−) B220+PNAhi GC B cells from each organ. ANOVA tests were performed comparing IgM− percentages between the different organs at each time point post-infection. Each bar represents mean ± SEM. n = 5–6 mice per group and time point. ns = not significant; *p<0.05; **p<0.01; ***p<0.001. (TIF)
    Preview · Dataset · Jul 2012

  • No preview · Conference Paper · May 2012

  • No preview · Article · Mar 2012 · Alcohol (Fayetteville, N.Y.)
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    ABSTRACT: Known therapies for influenza A virus infection are complicated by the frequent emergence of resistance. A therapeutic strategy that may escape viral resistance is targeting host cellular mechanisms involved in viral replication and pathogenesis. The endoplasmic reticulum (ER) stress response, also known as the unfolded protein response (UPR), is a primitive, evolutionary conserved molecular signaling cascade that has been implicated in multiple biological phenomena including innate immunity and the pathogenesis of certain viral infections. We investigated the effect of influenza A viral infection on ER stress pathways in lung epithelial cells. Influenza A virus induced ER stress in a pathway-specific manner. We showed that the virus activates the IRE1 pathway with little or no concomitant activation of the PERK and the ATF6 pathways. When we examined the effects of modulating the ER stress response on the virus, we found that the molecular chaperone tauroursodeoxycholic acid (TUDCA) significantly inhibits influenza A viral replication. In addition, a specific inhibitor of the IRE1 pathway also blocked viral replication. Our findings constitute the first evidence that ER stress plays a role in the pathogenesis of influenza A viral infection. Decreasing viral replication by modulating the host ER stress response is a novel strategy that has important therapeutic implications.
    Preview · Article · Dec 2011 · Journal of Biological Chemistry
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    ABSTRACT: The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell-extrinsic functions. Here, we show that increases in prostaglandin D(2) (PGD(2)) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration associated with virus-specific defects in T cell responses and was not a result of cell-intrinsic defect, rather it reflected the observed age-dependent increases in PGD(2) expression. Blocking PGD(2) function with small-molecule antagonists enhanced rDC migration, T cell responses, and survival. This effect correlated with upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. Our results suggest that inhibiting PGD(2) function may be a useful approach to enhance T cell responses against respiratory viruses in older humans.
    Preview · Article · Nov 2011 · The Journal of clinical investigation

  • No preview · Conference Paper · Nov 2011
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    ABSTRACT: Epidemiology studies have shown a clear correlation between chronic alcohol consumption and increases in incidence and severity of pulmonary infections. Consistent with these findings, our own recent studies using an animal model have demonstrated that chronic alcohol consumption leads to increased mortality, viral titers, pulmonary edema, and neutrophilia as well as significantly reduced virus-specific CD8 T cell responses during influenza virus infections. Together our results suggested that chronic alcohol alters both the innate and adaptive arms of the immune response therein contributing to the increased disease severity. In order to determine if these findings were unique to influenza virus infections or are more universal we developed a pulmonary bacterial infection model. To this end chronic ethanol consuming or water control mice were infected with Streptococcus, the most common bacteria associated with pneumonias in alcoholics, and the immune response, pulmonary inflammation, and disease severity monitored. Our preliminary results show increased mortality rates and pulmonary edema. Completion of our studies will allow us to definitively define common pathways that enhance pulmonary disease severity in alcoholics and therein offer potential targets for drug interventions.
    No preview · Conference Paper · Oct 2011
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    ABSTRACT: An immune response of appropriate magnitude should be robust enough to control pathogen spread but not simultaneously lead to immunopathology. Primary infection with influenza A virus (IAV) results in a localized pulmonary infection and inflammation and elicits an IAV-specific CD8 T cell immune response necessary for viral clearance. Clearance of IAV-infected cells, and recovery from infection, is mediated by perforin/granzyme B- and Fas/FasL-mediated mechanisms. We recently reported that TRAIL is another means by which IAV-specific CD8 T cells can kill IAV-infected cells. The current study examined the role of TRAIL in the pulmonary CD8 T cell response to a clinically significant IAV [A/PR/8/34 (PR8; H1N1)] infection (i.e., leads to observable, but limited, morbidity and mortality in wild-type [WT] mice). Compared with WT mice, IAV-infected Trail(-/-) mice experienced increased morbidity and mortality despite similar rates of viral clearance from the lungs. The increased morbidity and mortality in Trail(-/-) mice correlated with increased pulmonary pathology and inflammatory chemokine production. Analysis of lung-infiltrating lymphocytes revealed increased numbers of IAV-specific CD8 T cells in infected Trail(-/-) mice, which correlated with increased pulmonary cytotoxic activity and increased pulmonary expression of MIG and MIP-1α. In addition, there was decreased apoptosis and increased proliferation of IAV-specific CD8 T cells in the lungs of Trail(-/-) mice compared with WT mice. Together, these data suggest that TRAIL regulates the magnitude of the IAV-specific CD8 T cell response during a clinically significant IAV infection to decrease the chance for infection-induced immunopathology.
    Full-text · Article · Sep 2011 · The Journal of Immunology

Publication Stats

2k Citations
355.14 Total Impact Points


  • 2006-2014
    • University of Iowa
      • Department of Pathology
      Iowa City, Iowa, United States
  • 2009
    • Loyola University Medical Center
      • Department of Surgery
      Maywood, Illinois, United States
  • 2003
    • The Carter Center
      Atlanta, Georgia, United States
  • 1997-2002
    • The University of Tennessee Medical Center at Knoxville
      Knoxville, Tennessee, United States
  • 2000-2001
    • University of Tennessee
      • Department of Microbiology
      Knoxville, Tennessee, United States