CD40-CD40 ligand interactions augment survival of normal mice, but not CD40 ligand knockout mice, challenged orally with Salmonella dublin

Interactions between CD40 expressed on macrophages and CD40 ligand expresse d on T lymphocytes can be an important signal for optimal macrophage activa tion. Previous studies have demonstrated that the optimal response against certain intracellular pathogens (e,g., Crytosporidium and Leishmania spp,) by macrophages requires CD40-CD40 ligand interactions, However, this findin g is not universal, since two recent reports utilizing CD40 knockout mice h ave shown no such contribution to the protective immune response against My cobacterium tuberculosis or Histoplasma capsulatum, We demonstrate here tha t CD40-CD40 ligand interactions are significant events in the protective re sponse against the intracellular pathogen Salmonella dublin in normal mice but not for animals genetically deficient in CD40 ligand expression. Treati ng BALB/c mice exogenously with a CD40 agonist (i,e., soluble trimeric CD40 ligand) increased resistance against a lethal, orally administered dose of S. dublin, Conversely, in vivo administration of a monoclonal antibody aga inst CD40 ligand to block endogenous CD40-CD40 ligand interactions resulted in a decreased resistance to salmonellosis, In contrast, CD40 ligand knock out mice demonstrated no increased susceptibility to salmonellosis, In vitr o treatment of Salmonella-infected macrophages from BALB/c mice with solubl e trimeric CD40 ligand resulted in an elevated production of interleukin 12 p70 by these cells, suggesting a mechanism whereby CD40-CD40 ligand interac tions might enhance protective immune responses to this pathogen, Taken tog ether, these studies strongly suggest that CD40-CD40 ligand interactions in normal mice play an important protective role in immune responses against the gram-negative, intracellular pathogen S. dublin.