B. Gilbertson et al., Anergy, IFN-gamma production, and apoptosis in terminal infection of mice with Mycobacterium avium, J IMMUNOL, 163(4), 1999, pp. 2073-2080
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.