Acquired immunity to heavy infection with Mycobacterium bovis bacillus Calmette-Guérin and its relationship to the development of nonspecific unresponsiveness in vitro

Abstract

Mice heavily infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rapidly generated an acquired cellular immune response to this infection, as characterized primarily by the emergence of a splenic T-cell population capable of passively transferring substantial levels of adoptive protection against a challenge infection with M. tuberculosis. The emergence of this protective T-cell population was temporally associated with considerable levels of DNA synthesis in vivo in both the spleen and liver, and with the development of an acquired capacity within the animal to express very high levels of nonspecific resistance to secondary intracellular bacterial infection. Concomitant with the emergence of this acquired response, splenic T cells from infected animals became severely unresponsive to blastogenic in vitro stimulation with the mitogen phytohemagglutinin, and possessed the capacity to suppress the responsiveness of normal T cells in cocultures. Both the unresponsiveness of T cells from infected mice and their immunosuppressive activity in vitro could be essentially ablated by supplementation of the tissue culture medium with a supernatant containing very high titers of the T-cell growth factor interleukin 2 (IL-2). Furthermore, T cells harvested from these animals at the peak of in vitro unresponsiveness exhibited a substantial capacity to absorb or consume IL-2 from IL-2-containing supernatants. It is hypothesized, on the basis of these findings, that mice heavily infected with BCG acquire an IL-2-dependent T-cell population within the spleen in response to this infection, and that the observed in vitro blastogenic unresponsiveness of spleen cells which contain this population may be an artefactual effect arising from the reduction or consumption of available IL-2 within the sustaining culture medium. The relevance of these findings is discussed with particular regard to clinical situations, such as lepromatous leprosy, in which restorative strategies involving the in vivo use of IL-2 are presently being postulated.