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  1. Article ; Online: Author Correction

    Mladen Jergović / Christopher P. Coplen / Jennifer L. Uhrlaub / David G. Besselsen / Shu Cheng / Megan J. Smithey / Janko Nikolich-Žugich

    Nature Communications, Vol 15, Iss 1, Pp 1-

    Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells

    2024  Volume 1

    Keywords Science ; Q
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells

    Mladen Jergović / Christopher P. Coplen / Jennifer L. Uhrlaub / David G. Besselsen / Shu Cheng / Megan J. Smithey / Janko Nikolich-Žugich

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 16

    Abstract: Abstract Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections ...

    Abstract Abstract Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.
    Keywords Science ; Q
    Subject code 570
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Competent immune responses to SARS-CoV-2 variants in older adults following two doses of mRNA vaccination

    Mladen Jergović / Jennifer L. Uhrlaub / Makiko Watanabe / Christine M. Bradshaw / Lisa M. White / Bonnie J. LaFleur / Taylor Edwards / Ryan Sprissler / Michael Worobey / Deepta Bhattacharya / Janko Nikolich-Žugich

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 8

    Abstract: mRNA-based SARS-CoV-2 vaccines can induce protective immunity in older individuals, but whether they encompass new variants is not clear. Here the authors assess mRNA vaccine responses in both younger ( ... 55) cohorts to find slightly ... ...

    Abstract mRNA-based SARS-CoV-2 vaccines can induce protective immunity in older individuals, but whether they encompass new variants is not clear. Here the authors assess mRNA vaccine responses in both younger (<50) and older (>55) cohorts to find slightly delayed humoral and cellular immunity in the latter but, more importantly, reactivity to multiple variants. (I understand an eTOC summary is provided, but unfortunately it does not conform with our format.)
    Keywords Science ; Q
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: MAVS regulates the quality of the antibody response to West-Nile Virus.

    Marvin O'Ketch / Spencer Williams / Cameron Larson / Jennifer L Uhrlaub / Rachel Wong / Brenna Hall / Neha R Deshpande / Dominik Schenten

    PLoS Pathogens, Vol 16, Iss 10, p e

    2020  Volume 1009009

    Abstract: A key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs). Insights into the functions of cytosolic PRRs such as the RNA-sensing Rig-I-like ... ...

    Abstract A key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs). Insights into the functions of cytosolic PRRs such as the RNA-sensing Rig-I-like receptors (RLRs) in the instruction of adaptive immunity are therefore critical to understand protective immunity to infections. West Nile virus (WNV) infection of mice deficent of RLR-signaling adaptor MAVS results in a defective adaptive immune response. While this finding suggests a role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-dependent innate immune response. To overcome these limitations, we have infected MAVS-deficient (MAVSKO) mice with a single-round-of-infection mutant of West Nile virus. We show that MAVSKO mice failed to produce an effective neutralizing antibody response to WNV despite normal antibody titers against the viral WNV-E protein. This defect occurred independently of antigen loads or overt pathology. The specificity of the antibody response in infected MAVSKO mice remained unchanged and was still dominated by antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. Instead, MAVSKO mice produced IgM antibodies, the dominant isotype controlling primary WNV infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A disconnect between precursor frequency, expansion potential, and site-specific CD4+ T cell responses in aged mice.

    Neha R Deshpande / Jennifer L Uhrlaub / Sing Sing Way / Janko Nikolich-Žugich / Michael S Kuhns

    PLoS ONE, Vol 13, Iss 6, p e

    2018  Volume 0198354

    Abstract: T cell recognition of peptides presented within self-major histocompatibility complex (pMHC) molecules is essential for long-lived protective immunity. As mice age the number of naïve CD4+ and CD8+ T cells declines. However, unlike for CD8+ T cells, ... ...

    Abstract T cell recognition of peptides presented within self-major histocompatibility complex (pMHC) molecules is essential for long-lived protective immunity. As mice age the number of naïve CD4+ and CD8+ T cells declines. However, unlike for CD8+ T cells, there are more naïve and memory phenotype CD4+ T cells that bind foreign pMHCII in old mice (18-22 months) than adults (12-15 weeks), suggesting increased promiscuity of pMHCII recognition with aging. Here we asked if CD4+ T cell responses to immunization or infection increase with aging since the magnitude of a CD4+ T cell response to a foreign pMHCII is proportional to the size of the precursor population in adult mice. We observed no difference in the number of pMHCII-specific CD4+ T cells in adult versus old mice for pooled secondary lymphoid organs after immunization, bacterial infection, or viral infection, but we did observe diminished numbers of pMHCII-specific CD4+ T cells in both the draining lymph node and brain of old mice after West Nile virus infection. These data indicate that an increased precursor frequency does not translate into more robust responses upon immunization or infection in old mice.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency

    Chulwoo Kim / Rohit R. Jadhav / Claire E. Gustafson / Megan J. Smithey / Alec J. Hirsch / Jennifer L. Uhrlaub / William H. Hildebrand / Janko Nikolich-Žugich / Cornelia M. Weyand / Jörg J. Goronzy

    Cell Reports, Vol 29, Iss 8, Pp 2202-2216.e

    2019  Volume 5

    Abstract: Summary: Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in T cells as contributing to this defect. To understand the impact of miR-181a ... ...

    Abstract Summary: Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in T cells as contributing to this defect. To understand the impact of miR-181a expression on antiviral responses, we examined LCMV infection in mice with miR-181ab1-deficient T cells. We found that miR-181a deficiency delays viral clearance, thereby biasing the immune response in favor of CD4 over CD8 T cells. Antigen-specific CD4 T cells in mice with miR-181a-deficient T cells expand more and have a broader TCR repertoire with preferential expansion of high-affinity T cells than in wild-type mice. Importantly, generation of antigen-specific miR-181a-deficient CD8 effector T cells is particularly impaired, resulting in lower frequencies of CD8 T cells in the liver even at time points when the infection has been cleared. Consistent with the mouse model, CD4 memory T cells in individuals infected with West Nile virus at older ages tend to be more frequent and of higher affinity. : T cell aging in humans is associated with progressive loss in miR-181a, the implications of which for antiviral immunity are unknown. Using mouse models, Kim et al. find that miR-181a deficiency in T cells reproduces many aging features including impaired effector T cell expansion, viral clearance, generation of tissue-residing T cells, and recall responses. Keywords: immunosenescence, antiviral response, microRNA, CD8 effector T cell, T cell repertoire, immune aging
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus.

    Jennifer L Uhrlaub / Vesna Pulko / Victor R DeFilippis / Rebecca Broeckel / Daniel N Streblow / Gary D Coleman / Byung S Park / John F Lindo / Ivan Vickers / Joshua J Anzinger / Janko Nikolich-Žugich

    PLoS Pathogens, Vol 12, Iss 10, p e

    2016  Volume 1005891

    Abstract: Chikungunya virus (CHIKV) is a re-emerging global pathogen with pandemic potential, which causes fever, rash and debilitating arthralgia. Older adults over 65 years are particularly susceptible to severe and chronic CHIKV disease (CHIKVD), accounting for ...

    Abstract Chikungunya virus (CHIKV) is a re-emerging global pathogen with pandemic potential, which causes fever, rash and debilitating arthralgia. Older adults over 65 years are particularly susceptible to severe and chronic CHIKV disease (CHIKVD), accounting for >90% of all CHIKV-related deaths. There are currently no approved vaccines or antiviral treatments available to limit chronic CHIKVD. Here we show that in old mice excessive, dysregulated TGFβ production during acute infection leads to a reduced immune response and subsequent chronic disease. Humans suffering from CHIKV infection also exhibited high TGFβ levels and a pronounced age-related defect in neutralizing anti-CHIKV antibody production. In vivo reduction of TGFβ levels minimized acute joint swelling, restored neutralizing antibody production and diminished chronic joint pathology in old mice. This study identifies increased and dysregulated TGFβ secretion as one key mechanism contributing to the age-related loss of protective anti-CHIKV-immunity leading to chronic CHIKVD.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2016-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging.

    Luka Cicin-Sain / James D Brien / Jennifer L Uhrlaub / Anja Drabig / Thomas F Marandu / Janko Nikolich-Zugich

    PLoS Pathogens, Vol 8, Iss 8, p e

    2012  Volume 1002849

    Abstract: Prominent immune alterations associated with aging include the loss of naïve T-cell numbers, diversity and function. While genetic contributors and mechanistic details in the aging process have been addressed in multiple studies, the role of ... ...

    Abstract Prominent immune alterations associated with aging include the loss of naïve T-cell numbers, diversity and function. While genetic contributors and mechanistic details in the aging process have been addressed in multiple studies, the role of environmental agents in immune aging remains incompletely understood. From the standpoint of environmental infectious agents, latent cytomegalovirus (CMV) infection has been associated with an immune risk profile in the elderly humans, yet the cause-effect relationship of this association remains unclear. Here we present direct experimental evidence that mouse CMV (MCMV) infection results in select T-cell subset changes associated with immune aging, namely the increase of relative and absolute counts of CD8 T-cells in the blood, with a decreased representation of the naïve and the increased representation of the effector memory blood CD8 T-cells. Moreover, MCMV infection resulted in significantly weaker CD8 responses to superinfection with Influenza, Human Herpes Virus I or West-Nile-Virus, even 16 months following MCMV infection. These irreversible losses in T-cell function could not be observed in uninfected or in vaccinia virus-infected controls and were not due to the immune-evasive action of MCMV genes. Rather, the CD8 activation in draining lymph nodes upon viral challenge was decreased in MCMV infected mice and the immune response correlated directly to the frequency of the naïve and inversely to that of the effector cells in the blood CD8 pool. Therefore, latent MCMV infection resulted in pronounced changes of the T-cell compartment consistent with impaired naïve T-cell function.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Immune response to the West Nile virus in aged non-human primates.

    Anne M Wertheimer / Jennifer L Uhrlaub / Alec Hirsch / Guruprasad Medigeshi / Jerald Sprague / Alfred Legasse / Jennifer Wilk / Clayton A Wiley / Peter Didier / Robert B Tesh / Kristy O Murray / Michael K Axthelm / Scott W Wong / Janko Nikolich-Žugich

    PLoS ONE, Vol 5, Iss 12, p e

    2010  Volume 15514

    Abstract: BACKGROUND:Risk of encephalitis from West Nile virus (WNV) infection increases dramatically with age. Understanding the basis of this susceptibility requires development of suitable animal models. Here, we investigated the immune response to WNV in old ... ...

    Abstract BACKGROUND:Risk of encephalitis from West Nile virus (WNV) infection increases dramatically with age. Understanding the basis of this susceptibility requires development of suitable animal models. Here, we investigated the immune response to WNV in old non-human primates. METHODOLOGY/PRINCIPAL FINDINGS:We investigated clinical, immunological and virological correlates of WNV infection in aging non-human primates. Aged (17-30 yrs) and adult (6-9 yrs) Rhesus macaques (RM) were challenged with WNV in the presence or the absence of the mosquito salivary gland extract (SGE) to approximate natural infection. None of the 26 animals exhibited clinical signs of the disease. Quantitative PCR suggested discrete and short-lived viremia, but infectious virus was never isolated. There was markedly increased, age-independent, proliferation of CD3(-) non-B cells, followed by B-cell proliferation, which correlated to the loss of detectable WNV genomes. Moreover, animals primed with mosquito salivary gland extract exhibited reduced circulating WNV RNA. While we found the expected age-associated reduction in T cell proliferation, adaptive immunity did not correlate with infection outcome. That was further confirmed in a cohort of thymectomized and/or CD8 T-cell depleted Cynomolgus macaques (CM; N = 15), who also failed to develop WNV disease. CONCLUSIONS/SIGNIFICANCE:Results are consistent with strong and age-independent innate resistance of macaques against WNV challenge. This animal model is therefore not suitable for vaccine and therapeutic testing against WNV. However, understanding the basis of their innate resistance against WNV in macaques could provide helpful clues to improve anti-WNV protection of older adults.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2010-12-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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