Mucosal-associated invariant T (MAIT) cells mediate protective host responses in sepsis
- University of Utah, United States
Abstract
Sepsis is a systemic inflammatory response to infection and a leading cause of death. Mucosal-associated invariant T (MAIT) cells are innate-like T cells enriched in mucosal tissues that recognize bacterial ligands. We investigated MAIT cells during clinical and experimental sepsis, and their contribution to host responses. In experimental sepsis, MAIT-deficient mice had significantly increased mortality and bacterial load, and reduced tissue-specific cytokine responses. MAIT cells of WT mice expressed lower levels of IFN-γ and IL-17a during sepsis compared to sham surgery, changes not seen in non-MAIT T cells. MAIT cells of patients at sepsis presentation were significantly reduced in frequency compared to healthy donors, and were more activated, with decreased IFN-γ production, compared to both healthy donors and paired 90-day samples. Our data suggest that MAIT cells are highly activated and become dysfunctional during clinical sepsis, and contribute to tissue-specific cytokine responses that are protective against mortality during experimental sepsis.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (AI130378)
- Daniel T Leung
National Heart, Lung, and Blood Institute (HL092161)
- Matthew T Rondina
National Institute on Aging (AG040631)
- Matthew T Rondina
National Institute on Aging (AG048022)
- Matthew T Rondina
National Center for Advancing Translational Sciences (TL1TR002540)
- Daniel Labuz
National Institute of General Medical Sciences (HG008962)
- Cole P Anderson
University of Utah (3i Initiative Seed Grant)
- J Scott Hale
- Matthew T Rondina
- Daniel T Leung
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were maintained and experiments were performed in accordance with The University of Utah and Institutional Animal Care and Use Committee (IACUC) approved guidelines (protocol # 18-10012).
Human subjects: Each patient or a legally authorized representative provided written, informed consent. The University of Utah Institutional Review Board approved this study. (protocol #102638).
Reviewing Editor
- Nicola L Harris, Monash University, Australia
Publication history
- Received: January 30, 2020
- Accepted: November 9, 2020
- Accepted Manuscript published: November 9, 2020 (version 1)
- Version of Record published: November 20, 2020 (version 2)
Copyright
© 2020, Trivedi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody, which binds pathogens and commensal microbes. SIgA is a polymeric antibody, typically containing two copies of IgA that assemble with one joining-chain (JC) to form dimeric (d) IgA that is bound by the polymeric Ig-receptor ectodomain, called secretory component (SC). Here, we report the cryo-electron microscopy structures of murine SIgA and dIgA. Structures reveal two IgAs conjoined through four heavy-chain tailpieces and the JC that together form a β-sandwich-like fold. The two IgAs are bent and tilted with respect to each other, forming distinct concave and convex surfaces. In SIgA, SC is bound to one face, asymmetrically contacting both IgAs and JC. The bent and tilted arrangement of complex components limits the possible positions of both sets of antigen-binding fragments (Fabs) and preserves steric accessibility to receptor-binding sites, likely influencing antigen binding and effector functions.
