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

We have followed the course of experimental infection of mice with Mycobacterium avium over an extended period, assessing bacterial numbers and T cell responsiveness. When mice were infected intranasally, bacteria spread to the 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, produced IFN-gamma, After initial rapid growth, bacterial numbers slowly increased from similar to 10(7) at 6 wk to more than 5 x 10(8) at 28 wk, indicating that the resistance mechanisms so generated were not adequate to contain the infection. During infection, apoptosis of both CD4(+) and CD8(+) T cells, measured immediately ex vivo by staining with Annexin V, increased steadily. With some individual exceptions, there was a close correlation between apoptosis of CD4(+) cells and level of IFN-gamma production by cultured spleen cells. By 34 wk postinfection, there was an abrupt cessation of IFN-gamma production. No IL-4 was detected, ruling out a switch to Th2 profile. Subsequently, bacterial numbers increased still further to >5 x 10(9) per 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.