4-1BB (CD137) Is Required for Rapid Clearance ofListeria monocytogenesInfection

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Abstract
4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is a T-cell-costimulatory receptor that is expressed on activated T cells, dendritic cells, and NK cells. Little has been reported about its role in early host defense against bacterial infection. In this study, we report that 4-1BB-deficient (4-1BB−/−) mice are much more susceptible to Listeria monocytogenes (intracellular bacteria) infections than wild-type mice. Upon L. monocytogenes infection, 4-1BB−/− mice showed a lower survival rate, a higher bacterial burden in organs, and larger hepatic microabscesses than 4-1BB+/+ mice. 4-1BB−/− mice also had impairment in clearance of bacteria from the bloodstream. Neutrophils from 4-1BB+/+ mice constitutively expressed 4-1BB, which could be activated to induce intracellular Ca2+ influx by ligation with anti-4-1BB antibody. On the other hand, neutrophils from 4-1BB−/− mice were defective in reactive oxygen species generation, phagocytic activities, and intracellular Ca2+ mobilization. In addition, mice pretreated with anti-4-1BB monoclonal antibody were much more resistant to L. monocytogenes infection than control antibody-treated mice. Our results support the notion that 4-1BB may play a major role in host defense against intracellular pathogens through neutrophil activation.