Publications
58 results found
Taylor A, Harker JA, Chanthong K, et al., 2016, Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses, Immunity, Vol: 44, Pages: 274-286, ISSN: 1097-4180
Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
Lloyd CM, Harker JA, 2016, Location, Location, Location: Localized Memory Cells Take Residence in the Allergic Lung, IMMUNITY, Vol: 44, Pages: 13-15, ISSN: 1074-7613
- Author Web Link
- Cite
- Citations: 3
Harker J, Wong KA, Dolgoter A, et al., 2015, Cell-intrinsic gp130 Signaling on CD4+ T cells Shapes Long-lasting Antiviral Immunity, Journal of Immunology, ISSN: 1550-6606
The interleukin-6 (IL-6) cytokine family utilizes the common signal transduction molecule gp130, which can mediate a diverse range of outcomes. To clarify the role of gp130 signaling in vivo during acute viral infection we infected Cd4-cre Il6stfl/fl 4 mice, in which gp130 is conditionally ablated in T cells, with acute lymphocytic choriomeningitis virus (LCMV). We found that by day 12, but not at day 8, post infection the number of virus specific CD4+ 6 T cellswas reduced in the absence of gp130, and this was sustained for up to 2 months post infection. Additionally gp130 deficient TFH had lower expression of Maf, IL-21 and ICOS and this was accompanied by a reduction in the proportion of germinal center B cells and plasmablasts.Remarkably, two months post-infection the proportion of IgG2a/c+ 10 memory B cells and the systemic levels of LCMV-specific IgG2 Abs were dramatically decreased, while there was a corresponding increase in IgG1+ memory B cells and virus-specific IgG1 Abs. In the same animals Gp130 deficient virus specific CD8+ T cells showed a reduced proportion of memory cells, which expressed lower levels of Tcf7, and displayed diminished recall responses on secondary infection. Mixed bone marrow chimeras revealed that the aforementioned gp130 effects on CD4+ T cells were cell-intrinsic. Overall our data show that gp130 signaling in T cells influences the quantity and quality of long lasting CD4+ T cell responses as well as CD8+ T cell and antibody mediated immunity after acute viral infection.
Zuniga EI, Macal M, Lewis GM, et al., 2015, Innate and Adaptive Immune Regulation During Chronic Viral Infections, ANNUAL REVIEW OF VIROLOGY, VOL 2, Vol: 2, Pages: 573-597, ISSN: 2327-056X
- Author Web Link
- Cite
- Citations: 99
Harker JA, Dolgoter A, Wong KA, et al., 2014, T cell specific gp130 signalling orchestrates T cells and antibody responses after acute viral infection
Harker J, Dolgoter A, Lewis G, et al., 2014, Distinct and overlapping roles for cell intrinsic IL-6 and IL-27 signaling in promoting virus specific CD4+T cell numbers and function during acute and chronic viral infections, JOURNAL OF IMMUNOLOGY, Vol: 192, ISSN: 0022-1767
Harker JA, Yamaguchi Y, Culley FJ, et al., 2014, Delayed sequelae of neonatal RSV infection are dependent on cells of the innate immune system, Journal of Virology, ISSN: 0022-538X
Infection with respiratory syncytial virus (RSV) in neonatal mice leads to exacerbated disease if mice are re-infected with the same virus as adults. Both T cells and host MHC genotype contribute to this phenomenon, but the part played by innate immunity has not been defined. Since macrophages and natural killer (NK) cells play key roles in regulating inflammation during RSV infection of adult mice, we studied the role of these cells in exacerbated inflammation following neonatal RSV sensitization/adult re-infection. Compared to those undergoing primary adult infection, neonatally sensitized mice showed enhanced airway fluid levels of interleukin-6 (IL-6), interferon alpha (IFNα), CXCL1 (KC) and tumor necrosis factor alpha (TNFα) at 12-24h, and IL-4, IL-5, IFNγ and CCL11 (eotaxin) at day 4 after re-infection. Weight loss during re-infection was accompanied by an initial influx of NK cells and granulocytes into the airways and lungs, followed by T cells. NK depletion during re-infection attenuated weight loss, but did not alter T cell responses. Depleting alveolar macrophages with inhaled clodronate liposomes reduced both NK and T cell numbers and attenuated weight loss. These findings indicate a hitherto unappreciated role for the innate immune response in governing the pathogenic recall responses to RSV infection.
Tregoning JS, Wang B, McDonald JU, et al., 2013, Respiratory syncytial virus (RSV) infection during early life suppresses antibody responses by the induction of interferon gamma, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 104-104, ISSN: 0019-2805
Harker JA, Dolgoter A, Zuniga EI, 2013, Cell-Intrinsic IL-27 and gp130 Cytokine Receptor Signaling Regulates Virus-Specific CD4<SUP>+</SUP> T Cell Responses and Viral Control during Chronic Infection, IMMUNITY, Vol: 39, Pages: 548-559, ISSN: 1074-7613
- Author Web Link
- Cite
- Citations: 55
Harker J, Dolgoter A, Zuniga E, 2013, Cell intrinsic gp130 signaling is vital for virus specific CD4 T cell survival and interleukin 21 production during late stages of chronic viral infection, 100th Annual Meeting of the American-Association-of-Immunologists, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Tregoning JS, Wang BL, McDonald JU, et al., 2013, Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 5576-5581, ISSN: 0027-8424
- Author Web Link
- Open Access Link
- Cite
- Citations: 32
Yamaguchi Y, Harker JA, Wang B, et al., 2012, Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection, JOURNAL OF VIROLOGY, Vol: 86, Pages: 10456-10461, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 27
Zuniga EI, Harker JA, 2012, T-cell exhaustion due to persistent antigen: Quantity not quality?, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 42, Pages: 2285-2289, ISSN: 0014-2980
- Author Web Link
- Cite
- Citations: 14
Macal M, Lewis GM, Kunz S, et al., 2012, Plasmacytoid Dendritic Cells Are Productively Infected and Activated through TLR-7 Early after Arenavirus Infection, CELL HOST & MICROBE, Vol: 11, Pages: 617-630, ISSN: 1931-3128
- Author Web Link
- Cite
- Citations: 64
Harker JA, Lewis GM, Mack L, et al., 2011, Late Interleukin-6 Escalates T Follicular Helper Cell Responses and Controls a Chronic Viral Infection, SCIENCE, Vol: 334, Pages: 825-829, ISSN: 0036-8075
- Author Web Link
- Cite
- Citations: 259
Telcian AG, Laza-Stanca V, Edwards MR, et al., 2011, RSV-Induced Bronchial Epithelial Cell PD-L1 Expression Inhibits CD8<SUP>+</SUP> T Cell Nonspecific Antiviral Activity, JOURNAL OF INFECTIOUS DISEASES, Vol: 203, Pages: 85-94, ISSN: 0022-1899
- Author Web Link
- Cite
- Citations: 58
Tregoning JS, Yamaguchi Y, Harker JA, et al., 2010, T cell derived interferon gamma inhibits antibody responses during early life, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 52-52, ISSN: 0019-2805
Tregoning JS, Yamaguchi Y, Wang B, et al., 2010, Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent, JOURNAL OF IMMUNOLOGY, Vol: 185, Pages: 5384-5391, ISSN: 0022-1767
- Author Web Link
- Open Access Link
- Cite
- Citations: 33
Lee DCP, Harker JAE, Tregoning JS, et al., 2010, CD25<SUP>+</SUP> Natural Regulatory T Cells Are Critical in Limiting Innate and Adaptive Immunity and Resolving Disease following Respiratory Syncytial Virus Infection, JOURNAL OF VIROLOGY, Vol: 84, Pages: 8790-8798, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 115
Harker JA, Lee DCP, Yamaguchi Y, et al., 2010, Delivery of Cytokines by Recombinant Virus in Early Life Alters the Immune Response to Adult Lung Infection, JOURNAL OF VIROLOGY, Vol: 84, Pages: 5294-5302, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 24
Harker JA, Godlee A, Wahlsten JL, et al., 2010, Interleukin 18 Coexpression during Respiratory Syncytial Virus Infection Results in Enhanced Disease Mediated by Natural Killer Cells, JOURNAL OF VIROLOGY, Vol: 84, Pages: 4073-4082, ISSN: 0022-538X
- Author Web Link
- Cite
- Citations: 44
Pribul PK, Harker J, Wang B, et al., 2008, Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development, JOURNAL OF VIROLOGY, Vol: 82, Pages: 4441-4448, ISSN: 0022-538X
- Author Web Link
- Cite
- Citations: 157
Tregoning JS, Yamaguchi Y, Harker J, et al., 2008, The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice, JOURNAL OF VIROLOGY, Vol: 82, Pages: 4115-4124, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 96
Harker J, Bukreyev A, Collins PL, et al., 2007, Virally delivered Cytokines alter the immune response to future lung infections, JOURNAL OF VIROLOGY, Vol: 81, Pages: 13105-13111, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 25
Harker J, Tregoning JS, Bukreyev A, et al., 2005, Contrasting effects of virally expressed IFN-γ and IL-4 in neonatal and adult mice, IMMUNOLOGY, Vol: 116, Pages: 25-25, ISSN: 0019-2805
Wiles S, Clare S, Harker J, et al., 2005, Organ-specificity, colonization and clearance dynamics <i>in vivo</i> following oral challenges with the murine pathogen <i>Citrobacter rodentium</i> (vol 6, pg 963, 2004), CELLULAR MICROBIOLOGY, Vol: 7, Pages: 459-459, ISSN: 1462-5814
- Author Web Link
- Cite
- Citations: 11
Openshaw PJM, Tregoning J, Harker J, 2005, RSV 2005: Global impact, changing concepts, and new challenges., Viral Immunol, Vol: 18, Pages: 749-751, ISSN: 0882-8245
Wiles S, Clare S, Harker J, et al., 2004, Organ specificity, colonization and clearance dynamics <i>in vivo</i> following oral challenges with the murine pathogen <i>Citrobacter rodentium</i>, CELLULAR MICROBIOLOGY, Vol: 6, Pages: 963-972, ISSN: 1462-5814
- Author Web Link
- Cite
- Citations: 162
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.