COVID-19 severity and obesity: are MAIT cells a factor?

People with obesity have an increased risk of severe COVID-19: a meta-analysis by Popkin and colleagues¹ found that the odds ratio of people with obesity being hospitalised with COVID-19 was 2·13 when compared with those without obesity, and mortality was 48% higher in patients with obesity than in those without. This increased risk of severe disease is linked to higher rates of metabolic and cardiovascular complications.² Another major contributing factor is the presence of substantial immune dysregulation and chronic systemic inflammation. Obesity is associated with increased levels of numerous inflammatory mediators, including interleukin (IL)-1, IL-6, IL-17, and tumour necrosis factor α.³ These cytokines are also implicated in the pathogenesis of COVID-19.⁴ In addition to inflammation, obesity is associated with important defects in immune cells tasked with host protection, including natural killer cells and mucosal associated invariant T (MAIT) cells.5, 6

Several publications have highlighted MAIT cells as potentially having a crucial role in the host response to SARS-CoV-2.7, 8, 9, 10 In each of these studies, reduced peripheral serum MAIT-cell frequencies were observed in a COVID-19 severity-dependent manner (ie, with lower frequency associated with more severe COVID-19). Conversely, increased numbers of MAIT cells were noted in the lungs of patients with COVID-19 together with higher expression of MAIT-cell chemoattractants,7, 8 and increased levels of activated MAIT cells producing granzyme B were noted in patients with COVID-19.9, 10 Furthermore, importantly, after co-culturing MAIT cells with SARS-CoV-2-infected macrophages, increased activity of the MAIT cells producing granzyme B was observed, suggesting a possible ability of MAIT cells to respond to or directly kill infected cells.9, 10

A striking observation across these studies is the COVID-19 severity-dependent increase in the activation marker CD69.7, 9, 10 MAIT-cell activation (via CD69) was associated with prolonged hospitalisation, reduced PaO₂/FiO₂ ratio, and increased Simplified Acute Physiology Score (SAPS II), a measure of mortality risk for patients in the intensive care unit. These associations with COVID-19 severity might be due to altered MAIT-cell activity driving a proinflammatory response in patients with COVID-19. Pulmonary MAIT cells increase their expression of IL-17A,7, 9 a cytokine implicated in the pathogenesis of COVID-19 and the development of acute respiratory distress syndrome (ARDS; figure A, B ).11, 12 Moreover, analysis of an alveolar lavage single-cell dataset by Parrot and colleagues⁹ showed that MAIT cells were the predominant T-cell source of IL-17A.⁸

Figure.

Role of MAIT cells in COVID-19 and obesity

MAIT cells in (A) the lungs and (B) the peripheral blood of patients with COVID-19. (C) MAIT-cell response to adenovirus-vectored SARS-CoV-2 vaccine. (D) MAIT cells in the peripheral blood of people with obesity. CD=cluster of differentiation. DC=dendritic cell. IFN=interferon. IL=interleukin. MAIT cell=mucosal associated invariant T cell. PD-1=programmed cell death protein 1.

A study by Provine and colleagues¹³ highlighted MAIT cells as an important mediator for adenovirus-vectored vaccine immunogenicity to COVID-19. The authors found that, after administration of the ChAdOx1 nCoV-19 vaccine, MAIT cells in both mice and humans had increased levels of the activation marker CD69. These ChAdOx1-activated MAIT cells also produced increased levels of the antiviral molecules interferon (IFN)-γ and granzyme B (figure C). Furthermore, MAIT cells, in response to IFN-α and IL-18, were shown to support vaccine-induced CD8⁺ T-cell immunity, providing an important link between innate and adaptive immunity.¹³

These studies highlight a potentially crucial role for MAIT cells in the pathogenesis of COVID-19. In addition, the COVID-19-associated alterations in MAIT cells closely reflect those changes in MAIT cells observed in people with obesity.6, 14, 15 We and others have reported reduced MAIT-cell frequencies and an activated phenotype (increased CD69 and PD-1 expression) in people with obesity.⁶ MAIT cells from people with obesity also display a loss of IFN-γ, a cytokine that is key for antiviral responses, and elevated levels of the inflammatory cytokine IL-17, an established driver of ARDS (figure D).6, 15 We propose two open questions. First, could the poor outcome in people with obesity and COVID-19 be the result of a second hit from SARS-CoV-2 on the already compromised, proinflammatory MAIT-cell population? Second, could the obesity-related defects in MAIT cells affect the immune bridge proposed by Provine and colleagues and lead to diminished vaccine efficacy? In addressing these questions, clinicians and scientists will need to consider the contribution of this novel population of T cells to the prevention, pathogenesis, and treatment of COVID-19. Only then will we be able to harness fully the potential of MAIT cells or their cytokine products as targets for modifying the course of disease caused by SARS-CoV-2.

We declare no competing interests. DOS and AEH are funded by the Health Research Board, Ireland. AEH is funded by the National Children's Research Centre, Ireland.