Activation-dependent apoptosis in CD4+ T cells during murine AIDS.
The mechanism by which CD4+ T cells are depleted during HIV infection remains a matter of controversy. Recent reports have suggested that activation-induced apoptosis of antigen-specific CD4+ T cells may lead ultimately to depletion of this T cell subset during HIV infection. The murine retroviral model of AIDS (MAIDS) also displays progressive immunodeficiency, but depletion of the CD4+ T cell subset is not characteristic of the disease. We report that a fraction of splenic CD4+ T cells from 8- to 14-week MAIDS-infected C57B1/6 mice, but not normal mice, was undergoing apoptosis at the time of cell isolation. Typical apoptotic morphology and internucleosomal DNA fragmentation was seen in CD4+ T cells only from infected mice. Moreover, injection of anti-CD3 mAb enhanced DNA fragmentation in CD4+ T cells from infected but not normal mice, suggesting that the apoptosis in vivo in CD4+ T cells during MAIDS may be dependent on cell activation. Induction of apoptosis was associated with defective signaling through the TcR complex, since anti-CD3 stimulation in vitro of CD4+ T cells from infected mice caused a diminished calcium response, yet no cellular proliferation. Despite the occurrence of apoptosis in vivo in CD4+ T cells from MAIDS-infected mice, CD4+ T cells were not depleted during the course of disease. Thus, while apoptosis in CD4+ T cells is a characteristic of MAIDS immunodeficiency disease as well as HIV infections in humans, CD4+ T cell depletion is only observed in HIV infections. In view of the extensive lymphocyte expansion which occurs in vivo in MAIDS, the balance between activation-induced apoptosis and chronic cell proliferation may determine whether cell depletion is a characteristic feature of retrovirus-induced immunodeficiencies.
Cohen
D A
DA
Department of Microbiology and Immunology, University of Kentucky, College of Medicine, Lexington 40536-0084.
Fitzpatrick
E A
EA
Barve
S S
SS
Guthridge
J M
JM
Jacob
R J
RJ
Simmerman
L
L
Kaplan
A M
AM
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D016183:Murine Acquired Immunodeficiency Syndrome / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004247:DNA; D002118:Calcium