Cite as: T. Parrot et al., Sci. Immunol. 10.1126/sciimmunol.eabe1670 (2020). REPORTS First release: 28 September 2020 immunology.sciencemag.org (Page numbers not final at time of first release) 1 INTRODUCTION Severe acute respiratory syndrome (SARS) Coronavirus-19 (SARS-CoV-2) causes viral pneumonia and coronavirus dis- ease 2019 (COVID-19), which in some individuals progresses to acute respiratory distress syndrome (ARDS) characterized by aggressive inflammatory responses in the lower airways (reviewed in (1)). Severe COVID-19 is not only due to direct effects of the virus, but also in part to a misdirected host re- sponse with complex immune dysregulation of both innate and adaptive immune and inflammatory components (2, 3). The COVID-19 pandemic has been met with an unprece- dented research effort by academia as well as the pharmaceu- tical industry. Nevertheless, by mid-2020 many aspects of COVID-19 immunopathogenesis still remain poorly charac- terized. The majority of T cells respond in an adaptive fashion to peptide antigens governed by MHC-restriction, and the role of CD8 and CD4 T cell responses against COVID-19 has re- cently been demonstrated (4–10). However, the T cell com- partment also encompasses several unconventional invariant T cell subsets that have innate-like functions (11). Mucosa-as- sociated invariant T (MAIT) cells represent 1-10% of T cells in the circulation, have strong tissue homing characteristics and are particularly abundant in the liver and lung (reviewed in (12)). MAIT cells are activated by TCR recognition of micro- bial vitamin B2 (riboflavin) metabolites from a range of mi- crobes presented by MHC-Ib-related protein 1 (MR1) molecules (13). However, some MAIT cell functions can be activated or co-activated by cytokines such as IL-18 and type I IFNs (14, 15). MAIT cells rapidly produce IFN-γ, TNF- α, and IL-17, and mediate effective cytolytic function dependent on granzyme B (GrzB) (16–18). This broad effector profile CORONAVIRUS MAIT cell activation and dynamics associated with COVID- 19 disease severity Tiphaine Parrot 1* , Jean-Baptiste Gorin 1* , Andrea Ponzetta 1 , Kimia T. Maleki 1 , Tobias Kammann 1 , Johanna Emgård 1 , André Perez-Potti 1 , Takuya Sekine 1 , Olga Rivera-Ballesteros 1 , the Karolinska COVID-19 Study Group † , Sara Gredmark-Russ 1,2 , Olav Rooyackers 3,4 , Elin Folkesson 2,5 , Lars I. Eriksson 4,6 , Anna Norrby-Teglund 1 , Hans- Gustaf Ljunggren 1 , Niklas K. Björkström 1 , Soo Aleman 2,7 , Marcus Buggert 1 , Jonas Klingström 1 , Kristoffer Strålin 2,7 , and Johan K. Sandberg 1# 1 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. 2 Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden. 3 Department of Clinical Interventions and Technology, Karolinska Institutet, Stockholm, Sweden. 4 Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden. 5 Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. 6 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. 7 Division of Infectious Diseases and Dermatology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. *Equal contribution. †The Karolinska COVID-19 Study Group members are listed at the end of the Acknowledgments. *Correspondence: Dr. Johan K. Sandberg, Department of Medicine, Alfred Nobels Allé 8, Karolinska Institutet, 14152 Stockholm, Sweden. E-mail: johan.sandberg@ki.se Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa- associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69 high and CXCR3 low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis. Downloaded from https://www.science.org on December 05, 2021