CCR10-Regulated Mucosal Immune Responses Support Restoration of Lung Tissue Homeostasis after SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. While most patients can clear the infection and recover, some develop severe symptoms associated with dysregulated immune activation that leads to injury of lungs. Clinical studies found that severities of COVID-19 patients correlated with levels of mucosa-homing CCR10+ immunoglobulin A (IgA) antibody-secreting cells (IgA-ASCs) while recovery was linked to expansion of CCR10+ type 2 innate lymphoid cells (ILC2s). However, exact roles of CCR10-regulated mucosal immune responses in SARS-CoV-2 infection and pathology are not clear. Here, we addressed these questions using CCR10-knockout (KO) mice infected with a mouse-adapted strain of SARS-CoV-2. SARS-CoV-2-infected CCR10-KO mice had reduced IgA-ASCs but increased ILCs and T cells in lungs compared to control wild-type (WT) mice. However, CCR10-KO mice cleared SARS-CoV-2 as efficiently as WT mice, suggesting that CCR10-regulated mucosal immune responses are not critical for viral clearance. On the other hand, CCR10-KO mice, particularly males, were impaired in recovery from SARS-CoV-2-induced lung damages due to the immune dysregulation. Intranasal immunization overcame defective mucosal immune responses and prevented SARS-CoV-2-induced lung pathology in CCR10-KO mice. Our results revealed an important role of CCR10-regulated mucosal immune responses in restoration of lung homeostasis after SARS-CoV-2 infection.