Lung ICAMs and VCAM-1 in Innate and Adaptive Immunity to Influenza Infections: Unexpected Findings and Implications for Vaccination Strategies.

The β2 integrin ligands ICAM-1 ICAM-2 and the endothelial VLA-4 integrin ligand VCAM-1 are constitutively expressed on different lung vessels and on high endothelial venules. ICAMs are also ubiquitously expressed by many antigen presenting leukocytes and have been traditionally suggested as critical for the various antigen-specific immune synapses. Loss of both ICAMs reduces the ability of patrolling monocytes and Tregs to patrol the lung vasculature at steady state. Our new findings suggest, however, that in terms of innate leukocyte trafficking into the lung lamina propria both constitutively expressed and virus-induced vascular VCAM-1 can functionally compensate for the loss of these ICAMs. In a mouse model for influenza infection, neutrophil and NK cell recruitment and clearance of influenza remained normal in mice deficient in both ICAMs. Strikingly, these mice also mounted normal influenza specific CD8 proliferation and differentiation and normally combated secondary influenza infection indicating that the presence of ICAMs on conventional dendritic cells is not required for their immune synapse formation, as previously suggested. Furthermore, long lasting humoral responses critical for protection from a secondary homosubtypic influenza infection were also normal in mice deficient in both ICAMs. Collectively, our results suggest that the expression of ICAM-1 and ICAM-2 on lung endothelial and epithelial cells, as well as on DCs and B cells is not critical for the generation of innate or adaptive anti-viral immunity in the lungs. Our findings also suggest that endothelial VCAM-1 can substitute for the functions of vascular ICAMs in leukocyte trafficking into various lung compartments.