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4-1BB (CD137) Is Required for Rapid Clearance of Listeria monocytogenes Infection

Lee, Sang-C., Ju, Seong-A., Pack, Ha-N., Heo, Sook-K., Suh, Jae-H., Park, Sang-M., Choi, Boem-K., Kwon, Byoung S., Kim, Byung S.
Infection and immunity 2005 v.73 no.8 pp. 5144-5151
Listeria monocytogenes, T-lymphocytes, bacteria, blood flow, calcium, dendritic cells, gene expression, mice, monoclonal antibodies, natural killer cells, neutrophils, pathogens, reactive oxygen species, survival rate, tumor necrosis factors
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[superscript -/-]) mice are much more susceptible to Listeria monocytogenes (intracellular bacteria) infections than wild-type mice. Upon L. monocytogenes infection, 4-1BB[superscript -/-] mice showed a lower survival rate, a higher bacterial burden in organs, and larger hepatic microabscesses than 4-1BB[superscript +/+] mice. 4-1BB[superscript -/-] mice also had impairment in clearance of bacteria from the bloodstream. Neutrophils from 4-1BB[superscript +/+] 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[superscript -/-] 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.