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Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation.

Carson WF, Ito T, Schaller M, Cavassani KA, Chensue SW, Kunkel SL - PLoS ONE (2011)

Bottom Line: Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells.These include increased production of T(H)2 cytokines in TH1 inflammation, and increased production of T(H)1 cytokines in TH2 inflammation.These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, United States of America. wfcarson@umich.edu

ABSTRACT
Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative) and TH2-(Schistosoma mansoni egg antigen) driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of T(H)2 cytokines in TH1 inflammation, and increased production of T(H)1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

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Percentage and total number of CD3+ CD4+ T cells in lungs of PPD-challenged mice.Lobes from sham and CLP RAG PPD-challenged mice were processed into a single-cell suspension and analyzed via flow cytometry for the presence of CD3+ CD4+ T cells. (A) Percentages of CD3+ CD4+ T cells were obtained by gating on the standard forward/side scatter profile of lymphocytes . (B) Total numbers of CD3+ CD4+ T cells were obtained by multiplying the percentages obtained via flow cytometry via the total viable cell count (hemacytometer & vital dye exclusion). Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.
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pone-0020385-g002: Percentage and total number of CD3+ CD4+ T cells in lungs of PPD-challenged mice.Lobes from sham and CLP RAG PPD-challenged mice were processed into a single-cell suspension and analyzed via flow cytometry for the presence of CD3+ CD4+ T cells. (A) Percentages of CD3+ CD4+ T cells were obtained by gating on the standard forward/side scatter profile of lymphocytes . (B) Total numbers of CD3+ CD4+ T cells were obtained by multiplying the percentages obtained via flow cytometry via the total viable cell count (hemacytometer & vital dye exclusion). Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.

Mentions: To determine if the reduction in granuloma size in CLP RAG mice was due to decreased numbers of adoptively transferred CD4+ T cells trafficking to the lung, flow cytometric analysis of lung tissue from sham and CLP RAG mice was performed. As RAG−/− mice do not contain any endogenous mature CD3+ CD4+ T cells, it is expected that any mature CD3+ CD4+ T cells observed in peripheral tissues via flow cytometry will be donor-derived and not from the recipient mouse. The percentage of CD3+ CD4+ T cells (expressed as a percentage of total viable lung lymphocytes) was significantly reduced in CLP RAG lungs as compared to sham RAG mice at four days following i.v. PPD-bead challenge (Fig. 2A). Additionally, total numbers of CD3+ CD4+ T cells of CLP RAG mice were significantly decreased as compared to sham RAG mice (Fig. 2B), which also reflected a reduction in the total number of viable leukocytes recovered from the lungs of CLP RAG mice (per lobe: 9.70×106±1.2 total cells for sham RAG, 3.86×106 ±0.4 total cells for CLP RAG, p<0.01).


Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation.

Carson WF, Ito T, Schaller M, Cavassani KA, Chensue SW, Kunkel SL - PLoS ONE (2011)

Percentage and total number of CD3+ CD4+ T cells in lungs of PPD-challenged mice.Lobes from sham and CLP RAG PPD-challenged mice were processed into a single-cell suspension and analyzed via flow cytometry for the presence of CD3+ CD4+ T cells. (A) Percentages of CD3+ CD4+ T cells were obtained by gating on the standard forward/side scatter profile of lymphocytes . (B) Total numbers of CD3+ CD4+ T cells were obtained by multiplying the percentages obtained via flow cytometry via the total viable cell count (hemacytometer & vital dye exclusion). Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105020&req=5

pone-0020385-g002: Percentage and total number of CD3+ CD4+ T cells in lungs of PPD-challenged mice.Lobes from sham and CLP RAG PPD-challenged mice were processed into a single-cell suspension and analyzed via flow cytometry for the presence of CD3+ CD4+ T cells. (A) Percentages of CD3+ CD4+ T cells were obtained by gating on the standard forward/side scatter profile of lymphocytes . (B) Total numbers of CD3+ CD4+ T cells were obtained by multiplying the percentages obtained via flow cytometry via the total viable cell count (hemacytometer & vital dye exclusion). Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.
Mentions: To determine if the reduction in granuloma size in CLP RAG mice was due to decreased numbers of adoptively transferred CD4+ T cells trafficking to the lung, flow cytometric analysis of lung tissue from sham and CLP RAG mice was performed. As RAG−/− mice do not contain any endogenous mature CD3+ CD4+ T cells, it is expected that any mature CD3+ CD4+ T cells observed in peripheral tissues via flow cytometry will be donor-derived and not from the recipient mouse. The percentage of CD3+ CD4+ T cells (expressed as a percentage of total viable lung lymphocytes) was significantly reduced in CLP RAG lungs as compared to sham RAG mice at four days following i.v. PPD-bead challenge (Fig. 2A). Additionally, total numbers of CD3+ CD4+ T cells of CLP RAG mice were significantly decreased as compared to sham RAG mice (Fig. 2B), which also reflected a reduction in the total number of viable leukocytes recovered from the lungs of CLP RAG mice (per lobe: 9.70×106±1.2 total cells for sham RAG, 3.86×106 ±0.4 total cells for CLP RAG, p<0.01).

Bottom Line: Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells.These include increased production of T(H)2 cytokines in TH1 inflammation, and increased production of T(H)1 cytokines in TH2 inflammation.These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, United States of America. wfcarson@umich.edu

ABSTRACT
Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative) and TH2-(Schistosoma mansoni egg antigen) driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of T(H)2 cytokines in TH1 inflammation, and increased production of T(H)1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

Show MeSH
Related in: MedlinePlus