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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 195-202
CD4 T lymphocytes are primed to express Fas ligand by CD4
cross-linking and to contribute to CD8 T-cell apoptosis via
Fas/FasL death signaling pathway
Masaki Tateyama,
Naoki Oyaizu,
Thomas W. McCloskey,
Soe Than, and
Savita Pahwa
From the Department of Pediatrics, Division of Allergy/Immunology,
North Shore University Hospital-New York University School of Medicine,
Manhasset, New York; and the Department of Retroviral Regulation,
Division of Medical Research, Tokyo Medical and Dental University,
Bunkyo-ku, Yushima, Tokyo, Japan.
CD4 molecules serve as coreceptors for the T-cell receptor
(TCR)/CD3 complex that are engaged coordinately with TCR
and facilitate antigen-specific T-cell activation leading to
interleukin 2 (IL-2) production and proliferation. However,
cross-ligation of CD4 molecules prior to TCR stimulation has been shown
to prime CD4 T cells to undergo apoptosis. Although in vivo and in
vitro experiments have implicated the involvement of Fas/FasL
interaction in this CD4 cross-linking (CD4XL)-induced apoptosis,
detailed mechanisms to account for cell death induction have not been
elucidated. In the present study, we demonstrate that CD4XL in purified
T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis
was observed in CD8+ T cells as well and was associated
with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent
apoptosis following cell-cell contact with FasL+ CD4 T
cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with
restoration of IL-2 production and prevented Bcl-x down-modulation. As
CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can
lead to the generation of FasL-expressing CD4+ T cells
that can lead to apoptosis of CD4 as well as CD8 T cells. These
findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.
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