COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19–driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS–CoV-2–driven ARDS.

Highlights d Unbiased scRNA-seq on thymic iNKT reveals discrete subsets in iNKT1 and iNKT2 d Transcriptomically defined iNKT2 cells comprise precursors to iNKT1 and iNKT17 d Most of thymic iNKT subsets seem to have the potential to egress the thymus d The transcription cofactor FHL2 controls specification of the iNKT1 effector fate

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