THE ROLE OF INTERLEUKIN-12 IN ACQUIRED-IMMUNITY TO MYCOBACTERIUM-TUBERCULOSIS INFECTION

The early phase of acquired cellular immunity to Mycobacterium tubercu losis infection is mediated by the emergence of protective CD4 T lymph ocytes that secrete cytokines including interferon-gamma (IFN-gamma), a molecule which is pivotal in the expression of resistance to tubercu losis. Recent evidence demonstrates that infection with M. tuberculosi s induces peripheral blood mononuclear cells to release the cytokine i nterleukin-12 (IL-12), a molecule that promotes the emergence of T-hel per type-1 (Th1), IFN-gamma-producing T cells. We demonstrate here tha t IL-12 mRNA expression was induced by M. tuberculosis infection both in vivo and in vitro and that exogenous administration of IL-12 to mic e transiently resulted in increased resistance to the infection. IL-12 also increased the production of IFN-gamma by both splenocytes derive d from infected animals treated in vivo and by antigen-stimulated CD4 cells from untreated infected animals, with maximal effects at times a ssociated with the expansion of antigen-specific CD4 T cells in vivo. In the absence of a T-cell response, as seen in SCID mice or nude mice , IL-12 only slightly augmented the moderate bacteriostatic capacity o f these immunocomprised mice. Neutralization of IL-12 by specific mono clonal antibodies resulted in a reduction in granuloma integrity and s lowing of the capacity of the animal to control bacterial growth.