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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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Decreased granuloma size in PPD-challenged CLP RAG lungs.RAG2−/− mice that received i.v. injections of splenic CD4+ T cells from sham surgery or CLP donor mice were sensitized i.p. with PPD emulsified in CFA, and fourteen days following sensitization were i.v. challenged with PPD-coated sepharose beads. Four days following bead challenge, mice were sacrificed, and lung lobes were processed in a standard manner for histological analysis. H&E stains of sham RAG (A&C) and CLP RAG (B&D) lungs are shown at 10x (A&B) and 40x (C&D) magnification. “Bead” indicates the presence of the antigen-coated sepharose bead. (E) Average granuloma size in sham and CLP PPD-bead challenged lungs. Morphometric analysis of granulomas in H&E slides, 10 granulomas per lung, 5 lungs per group. Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.
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pone-0020385-g001: Decreased granuloma size in PPD-challenged CLP RAG lungs.RAG2−/− mice that received i.v. injections of splenic CD4+ T cells from sham surgery or CLP donor mice were sensitized i.p. with PPD emulsified in CFA, and fourteen days following sensitization were i.v. challenged with PPD-coated sepharose beads. Four days following bead challenge, mice were sacrificed, and lung lobes were processed in a standard manner for histological analysis. H&E stains of sham RAG (A&C) and CLP RAG (B&D) lungs are shown at 10x (A&B) and 40x (C&D) magnification. “Bead” indicates the presence of the antigen-coated sepharose bead. (E) Average granuloma size in sham and CLP PPD-bead challenged lungs. Morphometric analysis of granulomas in H&E slides, 10 granulomas per lung, 5 lungs per group. Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.

Mentions: To assess the functional capacity of post-septic CD4+ T cells to mediate TH1-type granulomatous lung inflammation, RAG2−/− mice that received CD4+ T cells from sham (Sham RAG) or CLP mice (CLP RAG) were subjected to the PPD sensitization and bead challenge model. Four days following intravenous (i.v.) injection of PPD-coated beads, mice were sacrificed and lung histology was analyzed to assess severity of inflammation. While both sham RAG (Fig. 1A) and CLP RAG (Fig. 1B) mice were able to generate granulomatous lung inflammation in response to PPD-bead challenge, the granulomas in the CLP RAG mice were of a smaller diameter than their Sham RAG counterparts (Fig. 1B). Total cellularity appeared reduced in CLP RAG mice, however the composition of the granulomas appeared similar between sham RAG (Fig. 1C) and CLP RAG (Fig. 1D) lungs, composed of mononuclear cells, lymphocytes and neutrophils. Repeated analysis of multiple lung slides confirmed the reduced size of CLP RAG granulomas, with a significant reduction in granuloma size observed across all lungs analyzed (Fig. 1E).


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)

Decreased granuloma size in PPD-challenged CLP RAG lungs.RAG2−/− mice that received i.v. injections of splenic CD4+ T cells from sham surgery or CLP donor mice were sensitized i.p. with PPD emulsified in CFA, and fourteen days following sensitization were i.v. challenged with PPD-coated sepharose beads. Four days following bead challenge, mice were sacrificed, and lung lobes were processed in a standard manner for histological analysis. H&E stains of sham RAG (A&C) and CLP RAG (B&D) lungs are shown at 10x (A&B) and 40x (C&D) magnification. “Bead” indicates the presence of the antigen-coated sepharose bead. (E) Average granuloma size in sham and CLP PPD-bead challenged lungs. Morphometric analysis of granulomas in H&E slides, 10 granulomas per lung, 5 lungs per group. 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-g001: Decreased granuloma size in PPD-challenged CLP RAG lungs.RAG2−/− mice that received i.v. injections of splenic CD4+ T cells from sham surgery or CLP donor mice were sensitized i.p. with PPD emulsified in CFA, and fourteen days following sensitization were i.v. challenged with PPD-coated sepharose beads. Four days following bead challenge, mice were sacrificed, and lung lobes were processed in a standard manner for histological analysis. H&E stains of sham RAG (A&C) and CLP RAG (B&D) lungs are shown at 10x (A&B) and 40x (C&D) magnification. “Bead” indicates the presence of the antigen-coated sepharose bead. (E) Average granuloma size in sham and CLP PPD-bead challenged lungs. Morphometric analysis of granulomas in H&E slides, 10 granulomas per lung, 5 lungs per group. Data presented is representative of two separate experiments, n = 5 per group. (*) = p<0.05 vs. sham RAG.
Mentions: To assess the functional capacity of post-septic CD4+ T cells to mediate TH1-type granulomatous lung inflammation, RAG2−/− mice that received CD4+ T cells from sham (Sham RAG) or CLP mice (CLP RAG) were subjected to the PPD sensitization and bead challenge model. Four days following intravenous (i.v.) injection of PPD-coated beads, mice were sacrificed and lung histology was analyzed to assess severity of inflammation. While both sham RAG (Fig. 1A) and CLP RAG (Fig. 1B) mice were able to generate granulomatous lung inflammation in response to PPD-bead challenge, the granulomas in the CLP RAG mice were of a smaller diameter than their Sham RAG counterparts (Fig. 1B). Total cellularity appeared reduced in CLP RAG mice, however the composition of the granulomas appeared similar between sham RAG (Fig. 1C) and CLP RAG (Fig. 1D) lungs, composed of mononuclear cells, lymphocytes and neutrophils. Repeated analysis of multiple lung slides confirmed the reduced size of CLP RAG granulomas, with a significant reduction in granuloma size observed across all lungs analyzed (Fig. 1E).

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