T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis

Authors

  • R. V. Anantha,

    1. Division of General Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
    2. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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  • D. M. Mazzuca,

    1. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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  • S. X. Xu,

    1. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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  • S. A. Porcelli,

    1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA
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  • D. D. Fraser,

    1. Children's Health Research Institute, London, ON, Canada
    2. Lawson Health Research Institute, London Health Sciences Centre- Victoria Campus, London, ON, Canada
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  • C. M. Martin,

    1. Lawson Health Research Institute, London Health Sciences Centre- Victoria Campus, London, ON, Canada
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  • I. Welch,

    1. Department of Animal Care and Veterinary Services, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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  • T. Mele,

    1. Division of General Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
    2. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
    3. Lawson Health Research Institute, London Health Sciences Centre- Victoria Campus, London, ON, Canada
    4. Centre for Human Immunology, Western University, London, ON, Canada
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  • S. M. M. Haeryfar,

    Corresponding author
    1. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
    2. Centre for Human Immunology, Western University, London, ON, Canada
    • Correspondence: S. M. M. Haeryfar or J. K. McCormick, Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON, Canada N6A 5C1.

      E-mail: mansour.haeryfar@schulich.uwo.ca or john.mccormick@uwo.ca

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  • J. K. McCormick

    Corresponding author
    1. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
    2. Centre for Human Immunology, Western University, London, ON, Canada
    • Correspondence: S. M. M. Haeryfar or J. K. McCormick, Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON, Canada N6A 5C1.

      E-mail: mansour.haeryfar@schulich.uwo.ca or john.mccormick@uwo.ca

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Summary

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non-septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra-abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)-17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis.

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