CD1d- and MR1-Restricted T Cells in Sepsis

doi:10.3389/fimmu.2015.00401

Review

. 2015 Aug 12:6:401.

doi: 10.3389/fimmu.2015.00401. eCollection 2015.

CD1d- and MR1-Restricted T Cells in Sepsis

Peter A Szabo¹, Ram V Anantha², Christopher R Shaler¹, John K McCormick³, S M Mansour Haeryfar⁴

Affiliations

¹ Department of Microbiology and Immunology, Western University , London, ON , Canada.
² Department of Microbiology and Immunology, Western University , London, ON , Canada ; Division of General Surgery, Department of Medicine, Western University , London, ON , Canada.
³ Department of Microbiology and Immunology, Western University , London, ON , Canada ; Centre for Human Immunology, Western University , London, ON , Canada ; Lawson Health Research Institute , London, ON , Canada.
⁴ Department of Microbiology and Immunology, Western University , London, ON , Canada ; Centre for Human Immunology, Western University , London, ON , Canada ; Lawson Health Research Institute , London, ON , Canada ; Division of Clinical Immunology and Allergy, Department of Medicine, Western University , London, ON , Canada.

PMID: 26322041
PMCID: PMC4533011
DOI: 10.3389/fimmu.2015.00401

Review

CD1d- and MR1-Restricted T Cells in Sepsis

Peter A Szabo et al. Front Immunol. 2015.

. 2015 Aug 12:6:401.

doi: 10.3389/fimmu.2015.00401. eCollection 2015.

Authors

Peter A Szabo¹, Ram V Anantha², Christopher R Shaler¹, John K McCormick³, S M Mansour Haeryfar⁴

Affiliations

¹ Department of Microbiology and Immunology, Western University , London, ON , Canada.
² Department of Microbiology and Immunology, Western University , London, ON , Canada ; Division of General Surgery, Department of Medicine, Western University , London, ON , Canada.
³ Department of Microbiology and Immunology, Western University , London, ON , Canada ; Centre for Human Immunology, Western University , London, ON , Canada ; Lawson Health Research Institute , London, ON , Canada.
⁴ Department of Microbiology and Immunology, Western University , London, ON , Canada ; Centre for Human Immunology, Western University , London, ON , Canada ; Lawson Health Research Institute , London, ON , Canada ; Division of Clinical Immunology and Allergy, Department of Medicine, Western University , London, ON , Canada.

PMID: 26322041
PMCID: PMC4533011
DOI: 10.3389/fimmu.2015.00401

Abstract

Dysregulated immune responses to infection, such as those encountered in sepsis, can be catastrophic. Sepsis is typically triggered by an overwhelming systemic response to an infectious agent(s) and is associated with high morbidity and mortality even under optimal critical care. Recent studies have implicated unconventional, innate-like T lymphocytes, including CD1d- and MR1-restricted T cells as effectors and/or regulators of inflammatory responses during sepsis. These cell types are typified by invariant natural killer T (iNKT) cells, variant NKT (vNKT) cells, and mucosa-associated invariant T (MAIT) cells. iNKT and vNKT cells are CD1d-restricted, lipid-reactive cells with remarkable immunoregulatory properties. MAIT cells participate in antimicrobial defense, and are restricted by major histocompatibility complex-related protein 1 (MR1), which displays microbe-derived vitamin B metabolites. Importantly, NKT and MAIT cells are rapid and potent producers of immunomodulatory cytokines. Therefore, they may be considered attractive targets during the early hyperinflammatory phase of sepsis when immediate interventions are urgently needed, and also in later phases when adjuvant immunotherapies could potentially reverse the dangerous state of immunosuppression. We will highlight recent findings that point to the significance or the therapeutic potentials of NKT and MAIT cells in sepsis and will also discuss what lies ahead in research in this area.

Keywords: CD1d; LPS; MAIT cell; MR1; NKT cell; infection; sepsis; α-galactosylceramide.

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Figures

**Figure 1**
**iNKT cell activation pathways in sepsis**. Early in the course of the host response to bacterial pathogens involved in sepsis, the engulfment of these microbes by phagocytic cells generates pathogen-derived glycolipids that can be displayed by CD1d to induce iNKT cell activation. Phagocytic cells that have taken up bacteria and/or sensed PAMPs (e.g., LPS) through PRRs (e.g., TLR-4) secrete inflammatory cytokines. Some of these cytokines (e.g., TNF-α, IL-1, IL-6) are responsible for clinical manifestations of sepsis, while others (i.e., IL-12 and IL-18) can activate iNKT cells. The latter pathway often, but not always, requires CD1d-mediated presentation of endogenous glycolipids to iNKT cells. SAg-secreting bacteria, such as *Staphylococcus* spp. and *Streptococcus* spp. participating in Gram-positive bacterial sepsis, can directly activate iNKT cells. It is possible that bacterial PAMPs may be detected by iNKT cells. Finally, during or as a result of the septic insult, host cell damage leads to release and/or modification of endogenous glycolipids that can be potentially presented by CD1d to trigger iNKT cell activation in an iTCR-dependent manner. Once activated, iNKT cells produce pro-inflammatory cytokines, most notably IFN-γ that plays a pivotal role in sepsis-inflicted immunopathology. APC, antigen-presenting cell; CD, cluster of differentiation; DC, dendritic cell; IFN, interferon; IL, interleukin; iNKT, invariant natural killer T cell; iTCR, invariant T cell receptor; LPS, lipopolysaccharide; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; TLR, Toll-like receptor.

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References

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[1] Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity (2014) 40(4):463–75.10.1016/j.immuni.2014.04.001 - DOI - PubMed

[2] Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity (2014) 40(4):463–75.10.1016/j.immuni.2014.04.001 - DOI - PubMed

[3] Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol (2007) 25:297–336.10.1146/annurev.immunol.25.022106.141711 - DOI - PubMed

[4] Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol (2007) 25:297–336.10.1146/annurev.immunol.25.022106.141711 - DOI - PubMed

[5] Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol (2010) 11(3):197–206.10.1038/ni.1841 - DOI - PubMed

[6] Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol (2010) 11(3):197–206.10.1038/ni.1841 - DOI - PubMed

[7] Bendelac A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J Exp Med (1995) 182(6):2091–6.10.1084/jem.182.6.2091 - DOI - PMC - PubMed

[8] Bendelac A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J Exp Med (1995) 182(6):2091–6.10.1084/jem.182.6.2091 - DOI - PMC - PubMed

[9] Smiley ST, Kaplan MH, Grusby MJ. Immunoglobulin E production in the absence of interleukin-4-secreting CD1-dependent cells. Science (1997) 275(5302):977–9.10.1126/science.275.5302.977 - DOI - PubMed

[10] Smiley ST, Kaplan MH, Grusby MJ. Immunoglobulin E production in the absence of interleukin-4-secreting CD1-dependent cells. Science (1997) 275(5302):977–9.10.1126/science.275.5302.977 - DOI - PubMed

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CD1d- and MR1-Restricted T Cells in Sepsis

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CD1d- and MR1-Restricted T Cells in Sepsis

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