Influenza infection recruits distinct waves of regulatory T cells to the lung that limit lung resident IgA+ B cells

• Published in: bioRxiv 2022-09
• Main Authors: Sjaastad, Louisa E, Owen, David L, Joo, Sookyong, Knutson, Todd P, O'connor, Christine H, Mcclusky, Braedan, Larue, Rebecca S, Langlois, Ryan A, Farrar, Michael A
• Format: Article
• Language: English
• Subjects: Coronaviruses; COVID-19; Foxp3 protein; Gene expression; Immunoglobulin A; Immunoregulation; Infections; Influenza; Interferon; Lungs; Lymphocytes B; Lymphocytes T; Peripheral blood; Respiration; T cell receptors
• DOI: 10.1101/2022.09.19.508325

The role of regulatory T cells (Tregs) in limiting responses to pathogens in tissues remains poorly described. We used scRNA-Seq and a newly generated Foxp3-lineage reporter line (Foxp3-iDTR mice) to track Tregs in the lungs and peripheral blood following infection with influenza virus. Few Tregs of any type were found in the lung at steady-state. Following influenza infection Tregs expressing a strong interferon-stimulated gene signature (ISG-Tregs) appeared by day 3, peaked by day 7, and largely disappeared by day 21 post-infection. A second diverse wave of tissue-repair-like Tregs (TR-Tregs) appeared by day 10 and were maintained through day 21 post-infection. These two distinct Treg subsets had different gene expression patterns and distinct TCR repertoires. To establish the role of Tregs during influenza infection, we acutely ablated Tregs at day 6 post-infection; this resulted in a significant increase in IgA+ B cells in the lung. To determine whether distinct Tregs subsets could also be observed in response to respiratory viral infections in humans we analyzed scRNA-Seq datasets of patients with COVID-19. Peripheral blood from healthy human volunteers had multiple Treg subsets defined by unique gene expression patterns, but few ISG-Tregs. In contrast, two distinct Tregs subsets were expanded in COVID-19 patients - ISG-Tregs and IL32 expressing Tregs (16-fold and 2-fold increased, respectively). ISG-Tregs were present at significantly higher levels in patients with mild versus severe COVID-19, while IL32 expressing Tregs showed the opposite pattern. Thus, the Treg response to respiratory viruses in humans is also diverse and correlates with disease outcome. Competing Interest Statement The authors have declared no competing interest.