CD8+ T Cell Response to Gammaherpesvirus Infection Mediates Inflammation and Fibrosis in Interferon Gamma Receptor-Deficient Mice
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{"title"=>"CD8+ T cell response to gammaherpesvirus infection mediates inflammation and fibrosis in interferon gamma receptor-deficient mice", "type"=>"journal", "authors"=>[{"first_name"=>"Brigid M.", "last_name"=>"O'Flaherty", "scopus_author_id"=>"56323641900"}, {"first_name"=>"Caline G.", "last_name"=>"Matar", "scopus_author_id"=>"56352378100"}, {"first_name"=>"Brian S.", "last_name"=>"Wakeman", "scopus_author_id"=>"56126406200"}, {"first_name"=>"Ana Patricia", "last_name"=>"Garcia", "scopus_author_id"=>"16401453800"}, {"first_name"=>"Carol A.", "last_name"=>"Wilke", "scopus_author_id"=>"7005107631"}, {"first_name"=>"Cynthia L.", "last_name"=>"Courtney", "scopus_author_id"=>"7006107096"}, {"first_name"=>"Bethany B.", "last_name"=>"Moore", "scopus_author_id"=>"7402320162"}, {"first_name"=>"Samuel H.", "last_name"=>"Speck", "scopus_author_id"=>"7005994168"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84943148969", "pui"=>"606226560", "doi"=>"10.1371/journal.pone.0135719", "sgr"=>"84943148969", "pmid"=>"26317335"}, "id"=>"b91d020f-2317-3a6d-848a-6d2ddb4c8f3a", "abstract"=>"Idiopathic pulmonary fibrosis (IPF), one of the most severe interstitial lung diseases, is a progressive fibrotic disorder of unknown etiology. However, there is growing appreciation for the role of viral infection in disease induction and/or progression. A small animal model of multi-organ fibrosis, which involves murine gammaherpesvirus (MHV68) infection of interferon gamma receptor deficient (IFNgammaR-/-) mice, has been utilized to model the association of gammaherpesvirus infections and lung fibrosis. Notably, several MHV68 mutants which fail to induce fibrosis have been identified. Our current study aimed to better define the role of the unique MHV68 gene, M1, in development of pulmonary fibrosis. We have previously shown that the M1 gene encodes a secreted protein which possesses superantigen-like function to drive the expansion and activation of Vbeta4+ CD8+ T cells. Here we show that M1-dependent fibrosis is correlated with heightened levels of inflammation in the lung. We observe an M1-dependent cellular infiltrate of innate immune cells with most striking differences at 28 days-post infection. Furthermore, in the absence of M1 protein expression we observed reduced CD8+ T cells and MHV68 epitope specific CD8+ T cells to the lungs-despite equivalent levels of viral replication between M1 null and wild type MHV68. Notably, backcrossing the IFNgammaR-/- onto the Balb/c background, which has previously been shown to exhibit weak MHV68-driven Vbeta4+ CD8+ T cell expansion, eliminated MHV68-induced fibrosis-further implicating the activated Vbeta4+ CD8+ T cell population in the induction of fibrosis. We further addressed the role that CD8+ T cells play in the induction of fibrosis by depleting CD8+ T cells, which protected the mice from fibrotic disease. Taken together these findings are consistent with the hypothesized role of Vbeta4+ CD8+ T cells as mediators of fibrotic disease in IFNgammaR-/- mice.", "link"=>"http://www.mendeley.com/research/cd8-t-cell-response-gammaherpesvirus-infection-mediates-inflammation-fibrosis-interferon-gamma-recep", "reader_count"=>6, "reader_count_by_academic_status"=>{"Librarian"=>1, "Researcher"=>2, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Librarian"=>1, "Researcher"=>2, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>1, "Medicine and Dentistry"=>1, "Business, Management and Accounting"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2233498"], "description"=>"<p>8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup> pfu MHV68 (WT or M1st) or were mock infected. (A) Mice were observed for weight change from starting weight, a loss of 20 percent or greater resulted in sacrifice. (B) Kaplan-Meier curves indicating mouse survival are shown. Significance was determined using log rank test with GraphPad software. <i>P</i> = 0.0027 for WT vs M1st infection.</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527746, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g001", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_M1_expression_is_associated_with_lethality_in_MHV68_infected_IFN_947_R_C57Bl_6_mice_/1527746", "title"=>"M1 expression is associated with lethality in MHV68 infected IFNγR-/- C57Bl/6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233502"], "description"=>"<p>8–12 week old WT or IFNγR-/- C57Bl/6 mice were intranasally infected with 1000 pfu MHV68 (WT or M1st) or were mock infected and sacrificed at 28 days post infection. Histological analysis was performed on lung tissues stained with hemotoxylin and eosin (H&E) or Masson’s Trichrome (MT). (A) Representative H&E stained sections are shown, scale bar = 100μm. Scores were determined for (A) pathology (mean and std. error are shown) from H&E sections and (B) fibrosis scores from MT sections, correlation was assessed using a Pearson’s Correlation test, showing R = 0.9929 at <i>P</i> = 0.0007, R<sup>2</sup> = 0.9858. Mock (n = 6), WT (n = 10), and M1st (n = 10).</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527750, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_M1_induced_fibrosis_in_IFN_947_R_C57Bl_6_mice_is_associated_with_heightened_levels_of_inflammation_in_lung_tissue_/1527750", "title"=>"M1 induced fibrosis in IFNγR-/- C57Bl/6 mice is associated with heightened levels of inflammation in lung tissue.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233504"], "description"=>"<p>8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup> pfu MHV68 (WT or M1st) or were mock infected and sacrificed at 28 days post infection. Whole lungs were assessed for (A) total number of cells (mean and std. error shown), (B) frequency of innate leukocytes (mean and std. error), and (C) frequency of innate populations (described in [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135719#pone.0135719.ref021\" target=\"_blank\">21</a>]). Statistics were performed using Kruskal-Wallis test with Dunn’s post test, <i>P</i> = 0.0463. Mock (n = 2), WT (n = 3), M1st (n = 4).</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527751, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g003", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Global_alterations_in_cellular_composition_of_lung_are_observed_in_fibrotic_IFN_947_R_C57Bl_6_mice_/1527751", "title"=>"Global alterations in cellular composition of lung are observed in fibrotic IFNγR-/- C57Bl/6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233505"], "description"=>"<p>8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup> pfu MHV68 (WT or M1st) and sacrificed at indicated times. (A) Lung titers from mice at days 4, 9, and 28 post infection (n = 7–10 mice/group from two independent experiments). (B) Spleen titers from mice at days 16 and 28 days post infection (n = 4–9 mice/group one or two independent experiments). (C) Viral persistence was measured by assessing cytopathic effect (CPE) induced by infected lung lysate plated on mouse embryonic fibroblasts (mean and std. error are shown).</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527753, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_absence_of_M1_expression_does_not_impact_acute_viral_replication_and_M1_is_not_required_for_viral_persistence_in_the_lung_/1527753", "title"=>"The absence of M1 expression does not impact acute viral replication, and M1 is not required for viral persistence in the lung.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233506"], "description"=>"<p>(A) Mink lung epithelial cells (MLEC-clone 32) stably transfected with a plasminogen activator inhibitor-1 fused to a luciferase reporter gene were infected with differing multiplicities of infection and assayed for luciferase activity (a read out of active TGFβ production). 8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup>pfu MHV68 (WT or M1st) or mock infected and sacrificed at 28 days post-infection (n = 3–4 mice/group). (B) lung lysates (30μg) were assessed for TGFβ1 expression by western blot (mock lane 1–3, WT lane 4–7, M1st lane 8–11), (C) normalized band density is shown.</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527754, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g005", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_absence_of_fibrosis_in_M1st_infected_IFN_947_R_C57Bl_6_mice_is_not_due_to_a_failure_in_profibrotic_mediator_TGF_946_1_expression_/1527754", "title"=>"The absence of fibrosis in M1st infected IFNγR-/- C57Bl/6 mice is not due to a failure in profibrotic mediator TGFβ1 expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233507"], "description"=>"<p>8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup> pfu MHV68 (WT or M1st) and sacrificed at 28 days post infection. Whole lungs were harvested and assessed for presence of CD8<sup>+</sup> T cell populations and effector function (n = 5 mice/group). Mean and std. error are shown for (A) absolute number of lung and CD8<sup>+</sup> T cells, (B&C) absolute number of tetramer specific and peptide responsive CD8<sup>+</sup> T cells, with MFI of cytokine expression, (D) absolute number of Vβ4<sup>+</sup> CD8<sup>+</sup> T cells and M1 responsive CD8<sup>+</sup> T cells. Statistics were measured using a Mann-Whitney 2 tailed test (* <i>P</i> = 0.0119, ** <i>P</i> = 0.0079, * <i>P</i> = <0.0004).</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527755, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g006", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_CD8_and_effector_CD8_T_cells_are_observed_in_absence_of_M1_expression_/1527755", "title"=>"Reduced CD8<sup>+</sup> and effector CD8<sup>+</sup> T cells are observed in absence of M1 expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233508"], "description"=>"<p>8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup> pfu MHV68 (WT or M1st) or were mock infected and sacrificed at indicated times (n = 1–13 mice/group from one or two independent experiments). Right and accessory lobes were harvested and assessed for hydroxyproline content at days 4, 9, 28, and 90 post-infection. Statistics were performed using Mann-Whitney 2 tailed test to compare WT and M1st (* <i>P</i> = 0.0159, *** <i>P</i> = 0.0008).</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527756, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Development_of_M1_dependent_fibrosis_in_IFN_R_C57Bl_6_mice_correlates_with_timing_and_kinetics_of_V_4_CD8_T_cell_expansion_/1527756", "title"=>"Development of M1 dependent fibrosis in IFNγR-/- C57Bl/6 mice correlates with timing and kinetics of Vβ4<sup>+</sup> CD8<sup>+</sup> T cell expansion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233509"], "description"=>"<p>8–12 week old IFNγR-/- Balbc mice were intranasally infected with 1000 pfu MHV68 (WT or M1st) or mock were infected and sacrificed at 28 days post infection (n = 3 mice/group). (A) Vβ4<sup>+</sup> CD8<sup>+</sup> T cell populations in spleen were assessed by flow cytometry. (B and C) Pathology scores were determined from H&E stained sections and fibrosis was evaluated with Masson’s trichrome stained tissue sections.</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527757, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g008", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IFN_947_R_Balb_c_mice_are_protected_from_MHV68_induced_fibrosis_/1527757", "title"=>"IFNγR-/- Balb/c mice are protected from MHV68 induced fibrosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233510"], "description"=>"<p>8–12 week old IFNγR-/- C57Bl/6 mice were intranasally infected with 1x10<sup>5</sup> pfu WT MHV68 and treated with either Rat IgG isotype or Rat αCD8 (clone YTS 169.4) antibodies prior to sacrifice (n = 4–5 mice/group). (A) CD8 depletion strategy is shown. (B) Peripheral blood was assessed for CD8<sup>+</sup> and Vβ4 <sup>+</sup> CD8 <sup>+</sup> T cell frequencies. (C) Mouse spleen weight at sacrifice and (D-F) pathology scores are shown. Scores were determined from H&E stained sections and fibrosis was evaluated with Masson’s Trichrome stained tissue sections.</p>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527758, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135719.g009", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Depletion_of_CD8_T_cells_ameliorates_MHV68_induced_fibrotic_disease_in_IFN_947_R_C57Bl_6_mice_/1527758", "title"=>"Depletion of CD8 T cells ameliorates MHV68 induced fibrotic disease in IFNγR-/- C57Bl/6 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-28 04:29:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/2233511", "https://ndownloader.figshare.com/files/2233512", "https://ndownloader.figshare.com/files/2233513", "https://ndownloader.figshare.com/files/2233514", "https://ndownloader.figshare.com/files/2233515"], "description"=>"<div><p>Idiopathic pulmonary fibrosis (IPF), one of the most severe interstitial lung diseases, is a progressive fibrotic disorder of unknown etiology. However, there is growing appreciation for the role of viral infection in disease induction and/or progression. A small animal model of multi-organ fibrosis, which involves murine gammaherpesvirus (MHV68) infection of interferon gamma receptor deficient (IFNγR-/-) mice, has been utilized to model the association of gammaherpesvirus infections and lung fibrosis. Notably, several MHV68 mutants which fail to induce fibrosis have been identified. Our current study aimed to better define the role of the unique MHV68 gene, M1, in development of pulmonary fibrosis. We have previously shown that the M1 gene encodes a secreted protein which possesses superantigen-like function to drive the expansion and activation of Vβ4<sup>+</sup> CD8<sup>+</sup> T cells. Here we show that M1-dependent fibrosis is correlated with heightened levels of inflammation in the lung. We observe an M1-dependent cellular infiltrate of innate immune cells with most striking differences at 28 days-post infection. Furthermore, in the absence of M1 protein expression we observed reduced CD8<sup>+</sup> T cells and MHV68 epitope specific CD8<sup>+</sup> T cells to the lungs—despite equivalent levels of viral replication between M1 null and wild type MHV68. Notably, backcrossing the IFNγR-/- onto the Balb/c background, which has previously been shown to exhibit weak MHV68-driven Vβ4<sup>+</sup> CD8<sup>+</sup> T cell expansion, eliminated MHV68-induced fibrosis—further implicating the activated Vβ4<sup>+</sup> CD8<sup>+</sup> T cell population in the induction of fibrosis. We further addressed the role that CD8<sup>+</sup> T cells play in the induction of fibrosis by depleting CD8<sup>+</sup> T cells, which protected the mice from fibrotic disease. Taken together these findings are consistent with the hypothesized role of Vβ4<sup>+</sup> CD8<sup>+</sup> T cells as mediators of fibrotic disease in IFNγR-/- mice.</p></div>", "links"=>[], "tags"=>["M 1 protein expression", "ipf", "fibrotic disease", "M 1 gene encodes", "Gammaherpesvirus Infection Mediates Inflammation", "type MHV 68.", "infection", "MHV 68 gene", "MHV 68 mutants", "role", "fibrosis", "MHV 68 epitope", "IFN γR mice", "interferon gamma receptor"], "article_id"=>1527759, "categories"=>["Uncategorised"], "users"=>["Brigid M. O’Flaherty", "Caline G. Matar", "Brian S. Wakeman", "Anapatricia Garcia", "Carol A. Wilke", "Cynthia L. Courtney", "Bethany B. Moore", "Samuel H. Speck"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0135719.s001", "https://dx.doi.org/10.1371/journal.pone.0135719.s002", "https://dx.doi.org/10.1371/journal.pone.0135719.s003", "https://dx.doi.org/10.1371/journal.pone.0135719.s004", "https://dx.doi.org/10.1371/journal.pone.0135719.s005"], "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CD8_T_Cell_Response_to_Gammaherpesvirus_Infection_Mediates_Inflammation_and_Fibrosis_in_Interferon_Gamma_Receptor_Deficient_Mice/1527759", "title"=>"CD8<sup>+</sup> T Cell Response to Gammaherpesvirus Infection Mediates Inflammation and Fibrosis in Interferon Gamma Receptor-Deficient Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-08-28 04:29:36"}

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  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"15", "full-text"=>"17", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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