Longitudinal analysis of mucosa‐associated invariant T cells in sepsis reveals their early numerical decline with prognostic implications and a progressive loss of antimicrobial functions

Abstract

Sepsis-elicited immunosuppression elevates the risk of secondary infections. We used a clinically relevant mouse model and serial peripheral blood samples from patients to assess the antimicrobial activities of mucosa-associated invariant T (MAIT) cells in sepsis. Hepatic and splenic MAIT cells from B6-MAIT CAST mice displayed increased CD69 expression and a robust interferon-c (IFNc) production capacity shortly after sublethal cecal ligation and puncture, but not at a late timepoint. Peripheral blood MAIT cell frequencies were reduced in septic patients at the time of intensive care unit (ICU) admission, and more dramatically so among nonsurvivors, suggesting the predictive usefulness of early MAIT cell enumeration. In addition, at ICU admission, MAIT cells from sepsis survivors launched stronger IFNc responses to several bacterial species compared with those from patients who subsequently died of sepsis. Of note, while low human leukocyte antigen (HLA)-DR + monocyte frequencies, widely regarded as a surrogate indicator of sepsis-induced immunosuppression, were gradually corrected, the numerical insufficiency of MAIT cells was not resolved over time, and their CD69 expression continued to decline. MAIT cell responses to bacterial pathogens, a major histocompatibility complex-related protein 1 (MR1) ligand, and interleukin (IL)-12 and IL-18 were also progressively lost during sepsis and did not recover by the time of ICU/hospital discharge. We propose that MAIT cell dysfunctions contribute to post-sepsis immunosuppression.

HLA‐DR+ mucosal‐associated invariant T cells predict poor prognosis in patients with sepsis: A prospective observational study

“…The percentage and absolute number of MAIT cells in peripheral blood samples from 72 patients with sepsis on day 1, 46 patients with sepsis on day 4 and 21 HCs were determined by flow cytometry. Consistent with the reported decrease in the percentage of MAIT cells in the peripheral blood of patients with sepsis in previous studies, 14–16,23 our data showed that the percentage and absolute numbers of MAIT cells were significantly lower in patients with sepsis both on days 1 and 4, compared to HCs. However, no differences between days 1 and 4 were noted (Figure 1A,B).…”

“…In the present study, we confirmed that CD69 expression on the surface of circulating MAIT cells in patients with sepsis was significantly upregulated. We also noted that the percentage and MFI of CD69 expression on MAIT cells of patients with sepsis on day 4 were lower than those on day 1, possibly due to tissue retention mediated by CD69, 16 unlike the late activation marker HLA‐DR which showed no difference between day 1 and day 4. In accordance with other studies of sepsis or group A streptococcal toxic shock syndrome, the activation markers CD38, CD69 and HLA‐DR of MAIT cells were increased at day 1, and the expression decreased in the convalescent phase for all except HLA‐DR 14,37 .…”

“…36 In the present study, we confirmed that CD69 expression on the surface of circulating MAIT cells in patients with sepsis was significantly upregulated. We also noted that the percentage and MFI of CD69 expression on MAIT cells of patients with sepsis on day 4 were lower than those on day 1, possibly due to tissue retention mediated by CD69, 16 unlike the late activation marker HLA-DR which showed no difference between day 1 and F I G U R E 4 ROC analyses for predicting 28-day mortality. MAIT, mucosal-associated invariant T; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; APACHE II, acute physiology and chronic health evaluation II; ROC, receiver operating characteristic; AUC, area under curve.…”

“…28,29 However, the initial mHLA-DR level in the early stage of sepsis might have little impact on mortality. 30 Furthermore, the activation of innate immunity cells occurs within the first hours of a septic process, and Choi J et al 16 demonstrated that the number of MAIT cells in the early stage might have a better predictive value than mHLA-DR. In addition, surface expression of HLA-DR on T lymphocytes significantly increased during early sepsis.…”

“…12 Previous studies have emphasized the protective role of MAIT cells in host antibacterial responses in vivo. 13 Their levels are also significantly decreased in patients with sepsis, [14][15][16] and the degree of decrease is associated with an elevated risk of intensive care unit (ICU)-acquired infections. 15 Furthermore, high expression levels of MAIT cell activation markers (CD69, CD38, CD137 and HLA-DR) and exhaustion markers (TIM-3 and LAG-3) have been documented in the early stages of sepsis.…”