"MHC class II on type II alveolar cells modulates type I interferon responses to pulmonary beta-coronavirus infection"

Kathleen Krauss and Laurence Eisenlohr

The type I interferon (IFN-I) response is a powerful signaling cascade, long recognized as a key contributor to antiviral immunity. However, IFN-I also contributes to immunopathology during viral infections. This dual action means that regulation of the IFN-I response is critical.

Class II major histocompatibility complex (MHCII) is best known for its role in presenting antigen to T cells. However, in this study, we propose an alternate role for MHCII, as a regulator of IFN-I signaling. MHCII is constitutively expressed on type 2 alveolar cells (AT2s); when we selectively ablated MHCII on AT2s in mice (AT2MHCII-), we found that they lost less weight after being infected with the natural mouse beta-coronavirus murine hepatitis virus 1 (MHV-1). AT2MHCII- mice also had lower levels of IFN-I in their lungs at 2 dpi. However, AT2MHCII- mice show no difference in viral burden in their lungs at the same time point.

From these data, we have constructed a model wherein AT2 MHCII acts as a positive regulator of IFN-I production. Since most IFN-I released in response to in vivo infection is produced by plasmacytoid dendritic cells (pDCs), our model proposes AT2s provoke pDCs to release more IFN-I. We propose this regulation occurs via signaling through lymphocyte-activation gene 3 (LAG3), a CD4 analog which serves as an alternate coreceptor for MHCII and is expressed on pDCs. Further investigation of this signaling axis could lead to improved understanding of the regulation of IFN-I signaling and therefore symptom burden in pulmonary viral infections.