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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 SEA-challenged mice.Lobes from sham and CLP RAG SEA-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 total lymphocytes based on forward/side scatter profile. (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-g005: Percentage and total number of CD3+ CD4+ T cells in lungs of SEA-challenged mice.Lobes from sham and CLP RAG SEA-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 total lymphocytes based on forward/side scatter profile. (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 increase in granuloma size in CLP RAG mice was due to increased 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. The percentage of CD3+ CD4+ T cells (expressed as a percentage of total viable lung lymphocytes) was equivalent in CLP RAG lungs as compared to sham RAG mice at four days following i.v. SEA-bead challenge (Fig. 5A). In addition, total numbers of CD3+ CD4+ T cells were equivalent between sham and CLP RAG lungs, indicating that the apparent increase in SEA-granuloma size was not due to a local increase in infiltrating CD4+ T cells (Fig. 5B)


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 SEA-challenged mice.Lobes from sham and CLP RAG SEA-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 total lymphocytes based on forward/side scatter profile. (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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105020&req=5

pone-0020385-g005: Percentage and total number of CD3+ CD4+ T cells in lungs of SEA-challenged mice.Lobes from sham and CLP RAG SEA-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 total lymphocytes based on forward/side scatter profile. (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 increase in granuloma size in CLP RAG mice was due to increased 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. The percentage of CD3+ CD4+ T cells (expressed as a percentage of total viable lung lymphocytes) was equivalent in CLP RAG lungs as compared to sham RAG mice at four days following i.v. SEA-bead challenge (Fig. 5A). In addition, total numbers of CD3+ CD4+ T cells were equivalent between sham and CLP RAG lungs, indicating that the apparent increase in SEA-granuloma size was not due to a local increase in infiltrating CD4+ T cells (Fig. 5B)

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