Anergy, IFN-gamma production, and apoptosis in terminal infection of mice with Mycobacterium avium

We have followed the course of experimental infection of mice with Mycobact erium avium over an extended period, assessing bacterial numbers and T cell responsiveness. When mice were infected intranasally, bacteria spread to t he spleen and liver, but remained in highest numbers in the lungs. Both CD4 (+) and CD8(+) T cells, assayed at any time from 6-28 wk after infection, p roduced IFN-gamma, After initial rapid growth, bacterial numbers slowly inc reased from similar to 10(7) at 6 wk to more than 5 x 10(8) at 28 wk, indic ating that the resistance mechanisms so generated were not adequate to cont ain the infection. During infection, apoptosis of both CD4(+) and CD8(+) T cells, measured immediately ex vivo by staining with Annexin V, increased s teadily. With some individual exceptions, there was a close correlation bet ween apoptosis of CD4(+) cells and level of IFN-gamma production by culture d spleen cells. By 34 wk postinfection, there was an abrupt cessation of IF N-gamma production. No IL-4 was detected, ruling out a switch to Th2 profil e. Subsequently, bacterial numbers increased still further to >5 x 10(9) pe r lung, and the mice lost body weight and would have died if not killed for experimental or humane reasons. The possibility that T cells exposed over this prolonged period to extremely high doses of Ag may become tolerant by a process of terminal differentiation is discussed.