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,
,
*
Department of Pathology,
Committee on Immunology, and
Department of Medicine, University of Chicago, Chicago, IL 60637
To examine the role of CTLA-4 in controlling Ag-specific
CD8+ T cell activation, TCR-transgenic/CTLA-4 wild-type or
-deficient mice were generated in a recombination-activating gene
2-deficient background. Naive T cells from these mice responded
comparably whether or not CTLA-4 was expressed. In contrast, primed T
cells responded more vigorously if they lacked CTLA-4 expression. We
took advantage of the difference between naive and primed T cell
responses to approach the mechanism of CTLA-4 function. Single-cell
analyses demonstrated that a greater fraction of CTLA-4-deficient cells
responded to a fixed dose of Ag compared with CTLA-4-expressing cells,
whereas the magnitude of response per cell was comparable. A shift in
the dose-response curve to APCs was also observed such that fewer APCs
were required to activate CTLA-4-deficient T cells to produce
intracellular IFN-
and to proliferate. These results suggest that
CTLA-4 controls the threshold of productive TCR signaling. Biochemical
analysis comparing stimulated naive and primed TCR-transgenic cells
revealed no obvious differences in expression of total CTLA-4,
tyrosine-phosphorylated CTLA-4, and associated Src homology domain
2-containing protein tyrosine phosphatase. Thus, the biochemical
mechanism explaining the differential inhibitory effect of CTLA-4 on
naive and primed CD8+ T cells remains
unclear.
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