The Ikaros zinc finger transcription factor Aiolos promotes the formation of lung-resident memory CD8+ T cells 2257320

Abstract

Abstract Introduction Influenza A virus (IAV) is responsible for half of all pandemics since the early 1900s, and since 2024, influenza infection has caused over 27,000 deaths in the U.S. alone. The economic burden of influenza is estimated to be $11.2 billion yearly in the U.S, with direct medical costs accounting for $3.2 billion. As IAV’s rapid mutation heightens the risk for future pandemics, effective and durable vaccines are urgently needed. Current IAV vaccines generate neutralizing antibodies against mutation-prone external IAV proteins, limiting their longevity. Resident memory CD8+T cells (TRM) offer an alternative as they, like other T cells, can recognize conserved internal IAV proteins. Uniquely, TRM reside within peripheral tissues like the lungs, enabling rapid response against respiratory viruses like IAV, and making them ideal vaccine targets. However, the molecular pathways governing TRM formation remain incompletely understood. Methods Here, we identify the transcription factor Aiolos as a novel inducer of TRM formation. TCR-transgenic OT-I CD8+ T cells were adoptively transferred into CD8 knockout mice, which were then infected with PR8-OVA (murine-adapted IAV). Lungs were collected at the effector and memory timepoints for flow cytometric analysis. Results We found that Aiolos-deficient murine CD8+ T cells expressed less CD103–a canonical TRM marker that facilitates lung retention–compared to wild-type (WT) controls. There were indeed significantly fewer Aiolos-deficient CD8+ T cells residing in the lungs after IAV infection at the memory timepoint. Mechanistically, we observed that Aiolos-deficient CD8+ T cells express less TGFβR1 (a TRM inducer) and more Eomes (a TRM repressor) than WT cells. Conclusion Collectively, our preliminary data suggest that Aiolos enhances lung-resident TRM formation and is a strong candidate target for improving durable immunity against IAV infection. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)