CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis.

Cell migration and phagocytosis are both important for controlling Mycobacterium tuberculosis infection and are critically dependent on the reorganization of the cytoskeleton. Since CD44 is an adhesion molecule involved in inflammatory responses and is connected to the actin cytoskeleton, we investigated the role of CD44 in both these processes. Macrophage (Mphi) recruitment into M. tuberculosis-infected lungs and delayed-type hypersensitivity sites was impaired in CD44-deficient (CD44(-/-)) mice. In addition, the number of T lymphocytes and the concentration of the protective key cytokine IFN-gamma were reduced in the lungs of infected CD44(-/-) mice. The production of IFN-gamma by splenocytes of CD44(-/-) mice was profoundly increased upon antigen-specific stimulation. Flow cytometry analysis revealed that soluble CD44 can directly bind to virulent M. tuberculosis. Mycobacteria also interacted with Mphi-associated CD44, as reflected by reduced binding and internalization of bacilli by CD44(-/-) Mphis. This suggests that CD44 is a receptor on Mphis for binding of M. tuberculosis. CD44(-/-) mice displayed a decreased survival and an enhanced mycobacterial outgrowth in lungs and liver during pulmonary tuberculosis. In summary, we have identified CD44 as a new Mphi binding site for M. tuberculosis that mediates mycobacterial phagocytosis, Mphi recruitment, and protective immunity against pulmonary tuberculosis.