International Immunology, Vol 9, 925-934, Copyright © 1997 by Oxford University Press
M Fridkis-Hareli, D Teitelbaum, I Pecht, R Arnon and M Sela
Copolymer 1 (Cop 1), a synthetic copolymer of amino acids, effective in
suppression of experimental allergic encephalomyelitis (EAE) and myelin
basic protein (MBP), was shown to bind extensively and promiscuously to the
class II MHC molecules on antigen-presenting cells (APC) without prior
processing. In the case of human APC, binding has earlier been demonstrated
to DR but not DQ or class I molecules. In the present study, we examined
whether binding of Cop 1 and MBP affects MHC class II expression on the
cell membrane. Biotinylated derivatives of these antigens were used to
monitor their direct binding to MHC molecules on living APC by flow
cytometry using phycoerythrin-streptavidin, while the levels of MHC surface
expression were monitored by staining with FITC-conjugated anti-class I-
and class II-specific antibodies. When Cop 1 or MBP were incubated with the
APC, intensity of cell staining with anti-DR, but not with anti-DQ or
anti-class I antibodies, was significantly increased, compared to the
staining of control APC not reacted with these antigens. In contrast,
staining intensity was unaffected when p84-102, a human immunodominant
epitope of MBP, or ovalbumin (OVA), a protein which undergoes proteolytic
degradation prior to binding, were incubated with the APC. Cycloheximide, a
protein synthesis inhibitor, had no effect on the enhanced staining
intensity with anti-DR antibody of cells treated with Cop 1 or MBP, whereas
it inhibited the enhanced staining of both DR and DQ molecules caused by
the respective antibodies, in the absence of these antigens. Brefeldin A, a
protein transport inhibitor, lowered the levels of staining intensity with
anti-DR and anti-DQ antibodies in both cases, with and without antigen
added to the APC. Fluorescence microscopic analysis revealed that cells
incubated with Cop 1 or MBP, but not with p84-102 or OVA, exhibit both
bright staining of the cell membrane and clusters produced by the
aggregation of DR molecules with these antigens. Taken together, these
observations indicate that Cop 1 and MBP, due to their polyvalent
character, lead to increased fluorescence intensity of their complexes with
HLA-DR, possibly due to recruitment and clustering of previously
synthesized DR molecules. This can explain the efficient binding of these
antigens to the MHC class II molecules.
ARTICLES
Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
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