Jam-C(-/-) mice exhibit growth retardation and multilobular pneumonia concomitant with poor survival of the mice under conventional housing conditions. The deficient mice present a mega-oesophagus and have altered airway responsiveness. In addition, the number of circulating granulocytes is increased in Jam-C(-/-) mice as compared to control animals. These phenotypes probably reflect the different functions of JAM-C expressed by endothelial and mesenchymal cells. Indeed, the deregulation in the number of circulating granulocytes is caused by the lack of JAM-C expression on endothelial cells since rescuing endothelial expression of the protein in the Jam-C(-/-) mice is sufficient to restore homeostasis. More importantly, the rescue of vascular JAM-C expression is accompanied by better survival of deficient mice, suggesting that endothelial expression of JAM-C is mandatory for animal survival from opportunistic infections and fatal pneumonia.