TCR triggering of anergic CD4 T cells in murine AIDS induces apoptosis rather than cytokine synthesis and proliferation.
Murine AIDS (MAIDS) induced by infection of C57BL/6 mice with a mixture of retroviruses known as LP-BM5 is characterized by lymphadenopathy, splenomegaly, and T and B cell dysfunction. By labeling with bromodeoxyuridine in vivo, we found vigorous CD4 T cell proliferation during the initial stages of infection, yet a loss in their ability to function both in vivo and in vitro. In addition, a significant fraction of the CD4 T cell population in infected mice undergoes spontaneous apoptosis in vivo. Upon in vitro stimulation with anti-CD3 plus PMA, anergic CD4 T cells from mice with MAIDS fail to progress through the cell cycle (G0/G1 arrest), and a fraction of the cells undergoes apoptosis. The addition of IL-2 along with TCR-mediated stimulation not only fails to rescue CD4 T cells from apoptosis, but enhances activation-induced cell death. To further understand the regulation of the suicide pathway(s) of anergic CD4 T cells vs the cytokine synthesis pathway(s) of normal CD4 T cells, we evaluated their expression of Bcl-2 protein. As infection progresses, the expression of Bcl-2 among CD4 T cells declines and drops further when CD4 T cells are restimulated through the TCR in vitro. These results suggest that this CD4 T cell immunodeficiency in MAIDS includes a TCR-induced program of activation-induced cell death and an uncoupling from cytokine synthesis pathways and proliferation of CD4 T cells. The decline in Bcl-2 expression may be in part responsible for this reprogramming.
Muralidhar
G
G
Department of Biology, University of California, San Diego 92093, USA.
Koch
S
S
Broome
H E
HE
Swain
S L
SL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001483:Base Sequence; D001973:Bromodeoxyuridine / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002453:Cell Cycle / Q000276:immunology; D017635:Clonal Anergy / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D019254:Genes, bcl-2 / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D009052:Leukemia Virus, Murine; D007942:Leukemia, Experimental / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016183:Murine Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D012192:Retroviridae Infections / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D001973:Bromodeoxyuridine