<i>Tbx21</i> and <i>Foxp3</i> Are Epigenetically Stabilized in T-Bet⁺ Tregs That Transiently Accumulate in Influenza A Virus-Infected Lungs

• Main Authors: Yassin Elfaki, Juhao Yang, Julia Boehme, Kristin Schultz, Dunja Bruder, Christine S. Falk, Jochen Huehn, Stefan Floess
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: influenza A virus; Tregs; lung; inflammation; methylation; <i>Tbx21</i>
• Online Access: https://www.mdpi.com/1422-0067/22/14/7522

During influenza A virus (IAV) infections, CD4⁺ T cell responses within infected lungs mainly involve T helper 1 (Th1) and regulatory T cells (Tregs). Th1-mediated responses favor the co-expression of T-box transcription factor 21 (T-bet) in Foxp3⁺ Tregs, enabling the efficient Treg control of Th1 responses in infected tissues. So far, the exact accumulation kinetics of T cell subsets in the lungs and lung-draining lymph nodes (dLN) of IAV-infected mice is incompletely understood, and the epigenetic signature of Tregs accumulating in infected lungs has not been investigated. Here, we report that the total T cell and the two-step Treg accumulation in IAV-infected lungs is transient, whereas the change in the ratio of CD4⁺ to CD8⁺ T cells is more durable. Within lungs, the frequency of Tregs co-expressing T-bet is steadily, yet transiently, increasing with a peak at Day 7 post-infection. Interestingly, T-bet⁺ Tregs accumulating in IAV-infected lungs displayed a strongly demethylated <i>Tbx21</i> locus, similarly as in T-bet⁺ conventional T cells, and a fully demethylated Treg-specific demethylated region (TSDR) within the <i>Foxp3</i> locus. In summary, our data suggest that T-bet⁺ but not T-bet⁻ Tregs are epigenetically stabilized during IAV-induced infection in the lung.