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ROLE OF T CELLS FOR CYTOKINE PRODUCTION AND OUTCOME IN A MODEL OF ACUTE SEPTIC PERITONITIS

Reim, Daniel; Westenfelder, Kay; Kaiser-Moore, Simone; Schlautkötter, Sylvia; Holzmann, Bernhard; Weighardt, Heike

doi: 10.1097/SHK.0b013e31817fd02c
Basic Science Aspects
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Although it is generally accepted that early defense mechanisms are controlled by cells of the innate immune system, T cells were found to be crucial for host resistance against acute septic peritonitis. However, the mechanisms by which T cells mediate protection are not fully understood. Here, we demonstrate mice deficient for recombinase-activating gene (RAG) 1, which lack mature B and T cells, showed enhanced susceptibility and impaired bacterial clearance in a model of acute septic peritonitis. Whereas B-cell-deficient μMT mice showed no significant difference in the survival rate after peritonitis induction, T-cell-deficient Balb/c nude mice exhibited reduced survival. Importantly, analysis of cytokine production in both RAG-1-deficient and T-cell-deficient nude mice indicated strongly attenuated production of IL-12, interferon (IFN) γ, and IL-10 during sepsis. Reduced cytokine levels were detected both in serum and in organ extracts of septic mice. Direct analysis of T cells isolated from septic mice demonstrated that T cells respond to an acute septic challenge by increased production of IFN-γ and IL-10. Moreover, bacterial numbers in spleens of septic RAG-1-deficient mice were significantly increased as compared with controls, suggesting that T cells are engaged in the early antibacterial immune defense during sepsis, possibly via the production of IFN-γ. In summary, these results imply that T cells contribute to protective immune responses against acute systemic infections via their ability to produce crucial immune mediators.

ABBREVIATIONS-CASP-colon ascendens stent peritonitis; CLP-cecal ligation and puncture; CXCL1-chemokine (CXC motif) ligand 1; RAG-recombinase-activating gene; SOCS5-suppressor of cytokine signaling-5

Department of Surgery, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany

Received 29 Feb 2008; first review completed 25 Mar 2008; accepted in final form 5 May 2008

Address reprint requests to Heike Weighardt, Institut für umweltmedizinische Forschung an der Heinrich-Heine-Universität Düsseldorf, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany. E-mail: Heike.Weighardt@uni-duesseldorf.de.

Daniel Reim and Kay Westenfelder contributed equally to this work.

This study was supported by the Deutsche Forschungsgemeinschaft (grant no. We 2625/1-1 to H.W.) and the Kommission für Klinische Forschung, Klinikum rechts der Isar.

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INTRODUCTION

Sepsis is a complex pathophysiological response of the body to systemic infection and may result in severe disorders such as septic shock and multiple organ failure (1, 2). Although activation of the innate immune system by microbial pathogens and their products was reported to contribute to hyperinflammation and organ damage during sepsis, many aspects of sepsis immunopathogenesis remain unclear.

Bacterial infections are initially controlled by the innate immune system, which recognize conserved pattern associated microbial patterns via specific receptors such as Toll-like receptors (TLRs). Ligation of TLR leads to the induction of host antibacterial effector functions and to the induction of adaptive immune responses. The general concept of immune responses supports the view that the adaptive immune system is activated at later time points during infections, but several studies indicate a functional role of lymphocytes during the early phase of severe bacterial infections, including sepsis (3-7). Excessive lymphocyte apoptosis can be demonstrated in the early phase of sepsis (4, 8). Inhibition of lymphocyte apoptosis by caspase inhibitors or by adoptive transfer of bcl2 overexpressing lymphocytes results in a protective effect during sepsis (4). Transcriptional profiling of CD4-positive lymphocytes during sepsis indicates a time-dependent alteration of the phenotype of CD4-positive T cells leading to cell membrane rearrangement and induction of apoptotic processes (9, 10). Furthermore, deficiency of αβ-T cells using T-cell receptor (TCR) β knockout mice or mice treated with anti-TCR-β antibodies display resistance to sepsis induced by cecal ligation and puncture (CLP), which was associated with reduced hypothermia and decreased production of the proinflammatory cytokines IL-6 and macrophage inflammatory protein 2, indicating that lymphocytes are involved in inflammatory processes during sepsis (11). These findings are in agreement with clinical investigations showing that early after sepsis diagnosis, T cells display reduced proliferative responses upon CD3/CD28 stimulation and reduced production of TNF and interferon (IFN) γ. This correlates with sepsis lethality, indicating an important role of T lymphocytes during sepsis (12). However, the mechanisms by which T cells may contribute to host defense under acute septic conditions are not fully resolved.

In the present study, we aimed to further elucidate the mechanisms by which T cells may influence immune responses during severe septic peritonitis. We show that recombinase-activating gene (RAG) 1-deficient mice exhibit increased susceptibility to polymicrobial sepsis as compared with control mice. T-Cell-deficient but not B-cell-deficient mice display reduced survival rates as compared with wild-type mice. This was associated with reduced systemic and local production of IL-12, IFN-γ, and IL-10 in RAG-1-deficient and T-cell-deficient mice. Importantly, splenic T cells isolated from septic wild-type mice were found to produce IFN-γ and IL-10. Moreover, bacterial numbers in spleens of septic RAG-1-deficient mice were significantly increased as compared with controls. Thus, T-cell-derived cytokines may contribute to protective immune responses during sepsis.

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MATERIALS AND METHODS

Mouse strains and colon ascendens stent peritonitis model of polymicrobial septic peritonitis

RAG-1-deficient and B-cell-deficient μMT mice (both C57BL/6 background) were purchased from the Jackson Laboratory (Bar Harbor, Maine). T-Cell-deficient Balb/c nude mice and controls of Balb/c and C57BL/6 strains were purchased from Harlan Winckelmann (Borchem, Germany). Mice at 8 to 12 weeks of age were used for all experiments. Data were pooled from three independent experiments, each with a total number of four to six mice. The colon ascendens stent peritonitis (CASP) procedure used for induction of septic peritonitis was described in detail previously (13, 14). Briefly, the colon ascendens was exteriorized, and a 7/0 ethilon thread (Ethicon, Nordersted, Germany) was stitched through the antimesenteric portion of the colon ascendens approximately 10 mm distal of the ileocecal valve. A 16-gauge venous catheter was punctured antimesenterically through the colonic wall into the intestinal lumen directly proximal of the pretied knot and fixed. To ensure proper intraluminal position of the stent, stool was milked from the cecum into the colon ascendens until a small drop appeared. Fluid resuscitation of the animals was performed by flushing 0.5 mL sterile saline into the peritoneal cavity before closure of the abdominal wall. The experiments using animals were done with the permission of the Regierung von Oberbayern, Germany.

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Systemic cytokine and chemokine production

Serum samples (nine mice per group and time point) were collected before and 12 h after CASP surgery. Immune mediator concentrations were measured by enzyme-linked immunosorbent assay (ELISA) specific for TNF-α, IL-10, IL-12, and chemokine (CXC motif) ligand 1 (CXCL1; all from R&D Systems, Minneapolis, Minn).

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Isolation of splenic T cells

Spleens were collected before and 6 h after CASP induction and were pooled from three mice. T cells were isolated using a BD FACSAria cell sorter (BD Biosciences, Heidelberg, Germany) after staining with anti-CD90 antibodies. The purity of the cell populations was determined by flow cytometry analysis and was greater than 96%. RNA was prepared immediately after sorting using an RNeasy mini kit (Qiagen, Hilden, Germany). Real-time polymerase chain reaction (PCR) analysis was performed as described in the succeeding sentences.

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Real-time PCR analysis

Spleens and livers (six mice per group and time point) were collected at different time points (0 and 6 h) after sepsis induction and stored in RNAlater buffer (Qiagen). RNA extractions were carried out using the RNeasy mini kit (Qiagen) according to the manufacturer's instructions. First-strand cDNA was synthesized from 1 μg of total RNA using a mixture of oligo(dT)12-18 and random hexamer primers and Superscript reverse transcriptase (Invitrogen, Karlsruhe, Germany). The reaction was incubated for 60 min at 42 °C and terminated by heating to 95 °C for 5 min. SYBR-green master mix was used to detect accumulation of PCR products during cycling on an SDS7700 cycler (Applied Biosystems, Foster City, Calif). RNA expression levels of samples of septic animals were normalized to β-actin and were displayed as fold-change relative to samples of control mice used as the calibrator (set to 1). Primers for β-actin and IL-10 were designed using PrimerExpress software (Applied Biosystems). Primers for amplification of specific cDNA fragments were as follows: β-actin sense, 5′-ACCCACACTGTGCCCATCTAC-3′; β-actin antisense, 5'-AGCCAAGTCCAGACGCAGG-3′; IL-10 sense, 5′-TCACATCAGCTGCT-ACTCCT-3′; IL-10 antisense, 5′-ACAGTACAGAGCTAGGACAG-3′. Interferon γ was detected with TaqMan gene expression array Mm00801778_m1 (Applied Biosystems).

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Determination of bacterial load of peripheral organs

Spleens (nine mice per group and time point) were collected 12 h after CASP surgery. Serial dilutions of organ homogenates were prepared in phosphate-buffered saline and plated onto blood agar plates (BD Biosciences). Colony-forming units were counted after incubation at 37°C for 24 h and calculated as colony-forming units per whole organ.

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Statistical analysis

Statistical analysis of the survival experiments data was performed by the log-rank test. For statistical analyses of data for cytokine expression and bacterial burden, the Student t test or the Mann-Whitney U test was used, as indicated in the figure legends. Statistical analyses, including normal distribution of data, were performed with the GraphPad InStat 3 software. All data are expressed as mean + SEM. The level of significance was P < 0.05 and was denoted with an asterisk.

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RESULTS

Enhanced susceptibility of RAG-1-null and T-cell-deficient mice to acute polymicrobial peritonitis

Previous work investigating lymphocyte apoptosis has provided evidence for a protective role of T cells during severe bacterial infections such as sepsis (8). However, the mechanisms by which T cells may contribute to host defense under acute septic conditions are not fully resolved. To further analyze the contribution of lymphocyte subsets to the outcome of sepsis, mice were subjected to the CASP model, a clinically relevant model for acute polymicrobial peritonitis (13, 14). Recombinase-activating gene-deficient mice, which lack mature B and T cells, were subjected to CASP. The results in Figure 1 demonstrate that RAG-1-deficient mice showed significantly enhanced susceptibility to septic peritonitis. Whereas 50% of control mice survived peritonitis, all RAG-1-deficient mice died within the first 20 h after sepsis induction. To distinguish whether T or B cells or both are important to protect mice against septic peritonitis, mice deficient for either B (μMT) or T cells (Balb/c nude) were subjected to CASP. Whereas B-cell-deficient mice displayed similar survival kinetics as wild-typecontrols, T-cell-deficient mice showed significantly enhanced susceptibility to polymicrobial peritonitis (Fig. 1). These data show that T cells, but not B cells, play an important role for the outcome of acute polymicrobial peritonitis.

Fig. 1

Fig. 1

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Attenuated systemic cytokine levels in RAG-1-deficient and T-cell-deficient mice

To analyze the role of T lymphocytes during acute sepsis in more detail, the systemic immune reaction was assessed in RAG1-deficient and T-cell-deficient nude mice. Both strains show attenuated sepsis induced production of IL-12 and IL-10 as compared with controls 12 h a1fter sepsis onset (Figs. 2 and 3). We have shown previously that, at this time point, the cytokine response reaches plateau levels in the CASP model of septic peritonitis (15). In contrast, levels of TNF-α and the chemokine CXCL1 were not affected in both strains.

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Because IL-12 and IFN-γ are known to amplify each other's production, T-cell-deficient Balb/c nude mice were further analyzed for the production of IFN-γ 6h after sepsis induction using real-time PCR. This time point was chosen because mRNA levels were measured and because IFN-γ production was expected to precede IL-12 release. Notably, both spleens and kidneys of T-cell-deficient Balb/c nude mice displayed attenuated production of IFN-γ mRNA during septic peritonitis as compared with wild-type controls (Fig. 4A). Analysis of TNF-α and IL-12 protein production in kidney also revealed reduced IL-12 levels, whereas TNF-α production was not significantly altered (Fig. 4B). These data show that the enhanced susceptibility of T-cell-deficient mice to polymicrobial sepsis is associated with a substantially reduced expression of the cytokines IL-10 as well as IL-12 and IFN-γ.

Fig. 4

Fig. 4

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Cytokine production of T cells during septic peritonitis

To directly analyze the contribution of T cells to the sepsis-induced cytokine expression, splenic T cells of septic and control mice were isolated via flow cytometry and analyzed by real-time PCR without any further restimulation in vitro. As compared with T cells isolated from untreated controls, T cells from septic mice exhibited markedly elevated levels of both IL-10 and IFN-γ mRNA. Figure 5 shows the results of two individual experiments each performed with cells pooled from three mice. These results provide direct evidence that T cells are able to produce IL-10 and IFN-γ during acute polymicrobial sepsis.

Fig. 5

Fig. 5

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Reduced bacterial clearance in RAG-1-deficient mice

Interferon γ is known to activate microbial clearance by phagocytes and was shown to be crucial for resistance of mice against polymicrobial sepsis in the CASP model (14). We therefore addressed the question as to whether reduced production of IFN-γ in T-cell-deficient mice may be related to impaired bacterial clearance. Recombinase-activating gene 1-deficient and wild-type mice were subjected to the CASP procedure, and bacterial counts of spleens were determined 12 h later. The results in Figure 6 demonstrate a significantly increased bacterial burden in septic spleens of RAG-1-deficient animals as compared with controls. These findings are consistent with the view that the lack of T-cell-derived cytokines may lead to reduced bacterial clearance during sepsis.

Fig. 6

Fig. 6

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DISCUSSION

Although B and T lymphocytes are critical for the induction of adaptive immune responses, there is also evidence that they are involved in the early immune reaction during infections. In the present study, we have analyzed the mechanisms by which B and T lymphocytes may influence the immune response against polymicrobial sepsis in a well-defined murine sepsis model, CASP. Recombinase-activating gene 1-deficient mice and T-cell-deficient Balb/c nude mice, but not B-cell-deficient μMT mice, showed enhanced susceptibility to CASP. This points to an important role of T lymphocytes for resistance against the lethal effects of severe sepsis. In accordance with these findings, excessive lymphocyte apoptosis has been shown previously to represent a hallmark of sepsis. Moreover, adoptive transfer of either T or B lymphocytes that overexpress bcl-2 into RAG-1-deficient hosts was found to improve survival of sepsis, indicating that prolonged survival of lymphocytes exerts protective effects (4). In addition, the adoptive transfer of total splenocytes enhances survival of RAG-1-deficient mice during CLP (6), confirming a protective role of lymphocytes during sepsis. Moreover, recent data show that CD4 T cells play an important role in the early immune response against sepsis (16).

To elucidate the function of T cells during sepsis in more detail, cytokine production was analyzed in RAG-1-deficient and Balb/c nude mice and compared with controls. Whereas there was no difference in the production of the inflammatory cytokine TNF and the chemokine CXCL1, both strains displayed a marked reduction of systemic and/or local levels of IL-12, IFN-γ, and IL-10. The local immune response in kidneys of Balb/c nude mice revealed attenuated IL-12 levels and a reduction of sepsis-induced IFN-γ. Moreover, T-cell deficiency substantially impaired bacterial clearance in the spleen. The importance of IL-10, IL-12, and IFN-γ for the immune defense against sepsis was previously demonstrated (14, 17-20). The present study substantially extends these findings by demonstrating that T cells are crucial for the production of IL-10, IL-12, and IFN-γ during sepsis.

Previous studies have shown that deficiency of IL-12 or the IFN-γ receptor resulted in enhanced susceptibility to polymicrobial peritonitis induced by CASP (14, 18). Both IFN-γ and IL-12 were also shown to be critically involved in the antibacterial host defense in other sepsis models (19-22). Together with these data, the findings of the present study indicate that T cells are engaged in the early antibacterial immune defense during sepsis via the production of the proinflammatory mediators IL-12 and IFN-γ. Consistent with this notion, transgenic overexpression of SOCS5 was reported to lead to enhanced T-cell-derived IFN-γ during polymicrobial sepsis, which was found to contribute to improved survival of sepsis (23), demonstrating an important function of T-cell-derived IFN-γ to protective immune responses during sepsis. Moreover, the involvement of T cells in the production of proinflammatory mediators during sepsis was shown in αβ-TCR-deficient mice, where attenuated production of IL-6 and macrophage inflammatory protein 2 contributes to the reduced survival rates of these mice during CLP (11).

To analyze directly whether T cells may be activated during the initial phase of sepsis, activation of lymphocytes was analyzed 12 h after sepsis induction. Although B cells reacted to septic peritonitis with the up-regulation of CD80 and CD69 (data not shown), analysis of μMT mice clearly indicated that B cells are dispensable for survival of septic peritonitis. It is well established that human and murine B cells respond to TLR-inducing stimuli in vitro (24-27) and in vivo during virus infections and autoimmune processes (28, 29). In the current study, CD69 up-regulation was demonstrated on T cells of LPS-treated mice (data not shown). During sepsis, using the CLP model, up-regulation of CD69 on CD4-positive T cells can be demonstrated (10, 11). In contrast, sepsis induction by CASP did not lead to CD69 up-regulation, perhaps reflecting differences in signal strength during sepsis induction between the various sepsis models.

It is important to note, however, that T cells were able to produce IL-10 and IFN-γ directly ex vivo, thereby contributing to immune mediator production during sepsis. Consistent with our findings, TLR-2 stimulation of mouse TH1 cells was recently shown to induce IFN-γ production without additional TCR stimulation, and this effect was greatly enhanced by IL-12 (30). Moreover, the rapid up-regulation of IL-22 during sepsis, which is mainly produced by T cells, underlines a proinflammatory function of T cells during sepsis (31). Toll-like receptor may serve as costimulatory molecules on T cells because human memory T expresses TLR-2 and is able to produce IFN-γ in response to bacterial lipopeptide (32). Furthermore, TLRs are expressed by regulatory T cells (33, 34), which were also shown to be involved in the immune response against sepsis (35, 36). Thus, T cells may be able to directly react to TLR-induced stimuli, and therefore, this alternative pathway may result in T-cell stimulation independently of antigen receptor signals. Considered together, these results indicate that T cells are directly involved in cytokine production during sepsis.

The results of the present report provide compelling evidence that T-cell-produced cytokines play an important role for the host defense against severe sepsis. Specifically, T cells were found to markedly contribute to systemic and/or local levels of IL-12, IFN-γ, and IL-10. Thus, T cells may not only contribute to chronic immune reactions but also play an important role in acute infections, thereby contributing to the activation of phagocytes and the amplification of the immune response against invading pathogens, most likely through an antigen receptor-independent pathway. The clinical relevance of these findings is further supported by the results of previous patient investigations showing that reduced production of IFN-γ and TNF-α by T cells during the onset of sepsis correlates with lethality (12). Nevertheless, it should be considered that mouse models may not recapitulate all aspects of human sepsis because supportive therapies such as intravenous fluid resuscitation, mechanical ventilation, or administration of antibiotics cannot be provided.

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ACKNOWLEDGMENTS

The authors thank S. Beer, Ph.D. (Institute for Medical Microbiology, Heinrich-Heine University, Du¨sseldorf, Germany), for critically reading the article.

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Keywords:

T cells; interferon γ; IL-10; IL-12; antibacterial defense; colon ascendens stent peritonitis

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