Role of CD40 ligand in Mycobacterium avium infection

Mycobacterium avinm is a common opportunistic pathogen in immunocompromised patients such as those infected with human immunodeficiency virus. Althoug h M. avium is an intracellular organism replicating predominantly in macrop hages, disseminated M. avium infection is seen in AIDS patients with CD4(+) cell counts of <50 cells/mu l, suggesting a possible involvement of a T ce ll-macrophage interaction for the elimination of M. avium. To determine whe ther CD40-CD40 ligand (CD40L) interactions play a role in M. avium infectio n, we studied the ability of CD40L to restrict M. avium replication In huma n monocyte-derived macrophages (MDM) in vitro. MDM were infected with M. av ium and cocultured with CD40L-transfected 293 cells for 7 days. Intracellul ar growth of M. avium in these MDM was assessed by colony counting. CD40L-e xpressing cells inhibited growth of M. avium in MDM by 86.5% +/- 4.2% compa red to MDM cultured with control cells. These findings were verified by ass ays using purified, soluble recombinant human CD40L (CD40LT). CD40LT (5 mu g/ml) inhibited intracellular growth of M. avium by 76.9% +/- 18.0% compare d to cells treated with medium alone. Inhibition by CD40LT was reduced by m onoclonal antibodies (MAbs) against CD40 and CD40L. The inhibitory effect o f CD40LT was not accompanied by enhancement of interleukin-12 (IL-12) produ ction by M. avium-infected MDM, while CD40L-expressing cells stimulated IL- 12 production by these cells. Treatment of Ill. avium-infected mice with MA b against murine CD40L resulted in recovery of larger numbers of organisms (0.8 to 1.0 log) from the spleens, livers, and lungs of these animals compa red to infected mice which received normal immunoglobulin G. These results indicate that CD40-CD40L signaling may be an important step in host immune response against M. avinm infection.