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CD28 ligation in T-cell activation: evidence for two signal transduction
pathways
JA Ledbetter, JB Imboden, GL Schieven, LS Grosmaire, PS Rabinovitch, T Lindsten, CB Thompson and CH June
Oncogen Corporation, Seattle.
The CD28 homodimer is thought to function as a signal transducing receptor
during activation of T cells. Evidence is presented that the degree of
aggregation of CD28 on the cell surface regulates two distinct
CD28-associated signals. Binding of bivalent CD28 monoclonal antibody
(MoAb) 9.3 upregulates lymphokine production by messenger RNA (mRNA)
stabilization, without direct initiation of lymphokine mRNA transcription.
This signal was not dependent on inositol phospholipid production or
activation of a protein tyrosine kinase (PTK). In contrast, further
crosslinking of CD28 on the cell surface rapidly induced formation of large
amounts of inositol trisphosphate (InsP3) and increased cytoplasmic calcium
concentration [( Ca2+]i), but did not stimulate PTK. CD28 crosslinking
directly activated a subset of resting T cells, since CD25 (interleukin
[IL]-2 receptor alpha chain) mRNA was rapidly induced in purified T cells,
and proliferation, even without addition of exogenous IL-2, was sometimes
observed. CD25 expression was detected on the cell surface of approximately
20% of CD4+ T cells. The degree of CD28 aggregation required for activation
was investigated by preparing soluble 9.3 x 9.3 conjugates ranging in size
from approximately 300 Kd to greater than 1,000 Kd, and comparing their
function in T-cell proliferation assays with phorbol-12-myristate-13-
acetate (PMA), anti-CD3, or IL-2. There was a correlation between conjugate
size and proliferation with IL-2, whereas costimulation with PMA or CD3 was
optimized at a lower degree of CD28 aggregation. The inositol phospholipid
(InsP) generation and increase in [Ca2+]i after CD28 receptor aggregation
appeared to proceed through a pathway different from the CD3/T-cell
receptor (TCR) pathway since it was enhanced by pretreatment with PMA,
while the InsP and [Ca2+]i signal from crosslinking CD3 was suppressed by
PMA. Furthermore, the proliferation response to CD28 aggregation was
resistant to inhibition by CD3 modulation. Thus, CD28 aggregation appears
to trigger a phospholipase C activation pathway that differs from the
CD3/TCR-linked pathway.
Volume 75,
Issue 7,
pp. 1531-1539,
04/01/1990
Copyright © 1990 by The American Society of Hematology
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