International Immunology, Vol 10, 1347-1358, Copyright © 1998 by Oxford University Press
J Fayen, JH Huang, S Ferrone and ML Tykocinski
mAb with specificity for the alpha3 domain of HLA class I antigens, such as
mAb TP25.99 and W6/32, are capable of inhibiting the proliferation of
stimulated T cells in vitro by binding to their surface HLA class I
antigens. The inhibitory potential of another HLA class I alpha3
domain-specific mAb, A1.4, was evaluated. In contrast to mAb TP25.99 and
W6/32, which routinely inhibited superantigen (SEB) stimulation of T cells
by >90%, mAb A1.4 at equivalent concentrations demonstrated only 20-50%
inhibition. Univalent Fab fragments of all three mAb lacked inhibitory
activity. Interestingly, however, by combining univalent W6/32 (or TP25.99)
Fab fragments with intact, bivalent mAb A1.4 (at a non-inhibitory,
sub-threshold concentration of 1 microg/ml), significant inhibition of
SEB-driven T cell proliferation was obtained. Inhibition by the anti-HLA
class I mAb W6/32 and TP25.99 was evident even when SEB was used in
conjunction with paraformaldehyde- fixed HLA class I-, class II+ Daudi
cells, suggesting that the inhibitory activity of these mAb results from
direct HLA class I epitope engagement on the T cell. These findings suggest
that effective antibody-mediated induction of the HLA class I inhibitory
pathway within T cells is dependent upon two separable molecular triggers
at the T cell surface. The first can be delivered by univalent mAb
derivatives that engage one or more critical HLA class I epitope(s). The
second requires intact mAb, though seems to be less selective as to the HLA
class I specificity. This model may explain why some, but not all, anti-HLA
class I mAb are inhibitory when used singly. Achieving synergies between a
wider array of anti-HLA class I mAb and their derivatives may provide a
path for more effectively tapping into the HLA class I inhibitory pathway
in a therapeutic context.
ARTICLES
Negative signaling by anti-HLA class I antibodies is dependent upon two triggering events
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106-4943, USA.
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