Mucosal-Associated Invariant T (MAIT) Cells Are Highly Activated and Functionally Impaired in COVID-19 Patients

Abstract

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.

Natural killer cells and unconventional T cells in COVID-19

“…On the other hand, residual circulating MAIT cells showed a significant increase in expression of several activation markers (e.g. CD69 and granzyme B) [ 8 •• , 9 •• , 10 •• , 32 , 33 , 34 , 35 ]. Functionally, circulating MAIT cells are skewed towards a type 3 inflammatory state, and display impaired IFN-ɣ production potential and increased IL-17A release [ 9 •• , 10 •• ], similar to the Th17 skewing described for CD4 + T cells in severe COVID-19 [ 36 ].…”

The role of unconventional T cells in COVID-19

“…MAIT cells show signs of activation during the SARS-CoV-2 infection, though how this links with clinical outcome is unclear. In both mild and severe cases of COVID-19, increased expression of the early activation marker CD69 on MAIT cells and diminished expression of the homing receptor chemokine C-X-C motif receptor 3 (CXCR3) has been reported [ 71 , 87 , 88 , 90 ]. MAIT cells usually express CXCR3 which is involved in lung homing [ 90 ].…”

“…In a cohort of 43 COVID-19 patients and 25 healthy controls, circulating MAIT cells displayed reduced frequency and an activated phenotype in individuals with COVID-19, regardless of disease severity, as characterised by high expression of IL-17A, TNFα, CD38, CD69 and HLA-DR [ 88 ]. Elevated expression of the activation marker HLA-DR by MAIT cells correlated with disease severity, as measured by the Simplified Acute Physiology Score (SAPS) II score, which estimates the probability of mortality for ICU patients.…”

“…CD8 expression by MAIT cells was markedly lower in individuals with COVID-19. In vitro stimulation assays revealed an altered cytokine production profile and impaired cytotoxic function [ 88 ]. When MAIT cells were stimulated with E. coli , typical upregulation of IFNγ was observed but levels of TNFα and IL-17A were significantly lower in COVID-19-positive individuals compared to healthy controls.…”

“…MAIT cells have been shown to be recruited into the airways during SARS-CoV-2 infection and their activation is linked with worse clinical outcomes in COVID-19 [ 87 , 88 ]. One potential driving factor is that MAIT cells are a source of IL-17 in severe COVID-19 [ 86 ].…”