Supplementary Figure 3 – Proposed mechanism: ACKR2 decreased pulmonary tolerance to influenza A virus infection by reducing CCL5 levels and impairing the development of cellular and humoral antiviral responses and tissue protection. Left panel: WT mice: IAV infection triggers a significant neutrophilic inflammation in the lungs characterized by pronounced production of inflammatory mediators such as IL-6 leading to pulmonary dysfunction and death. iBALT formation favors the cellular (Th1 cells) and humoral (IgA-secreting plasma cells) adaptive antiviral immune responses against influenza virus, that contribute for the virus clearance in airways. ACKR2 expression is predominant on vascular endothelium of lung parenchyma where CCL5 is bound leading to a lower bioavailability of the chemokine, thus limiting CCR5 expressing leukocytes (Th1, B-cells, Treg) recruitment. Right panel: ACKR2-/- mice: IAV infection is milder, with reduced neutrophilic lung inflammation and respiratory dysfunction, lower viral load and greater survival. ACKR2 deficiency leads to increased abundance of CCL5 which promotes lung tolerance to IAV infection in two ways: (1) by enhancing adaptive cellular and humoral immune responses via recruitment of CCR5 expressing Th1 lymphocytes and IgA-producing plasma cells and iBALT induction, leading to decreased viral loads; and (2) by protecting lungs from tissue damage through higher secretion of IL-10 and recruitment of CCR5 positive Treg lymphocytes, contributing to pulmonary tissue adaptation and homeostasis restoration after IAV infection.