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Gwen Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637; and
Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA 19104
CTLA-4-mediated inhibition of T cell activation may be accomplished
by competition for ligands and/or by signals mediated through the
intracellular domain. Studies have implicated Tyr201 in the
cytoplasmic domain of CTLA-4 in regulating CTLA-4 signal transduction
and intracellular trafficking. To investigate the mechanism of CTLA-4
function in vivo, transgenes encoding wild-type CTLA-4 (FL), a mutant
lacking the cytoplasmic domain of CTLA-4 (
CTLA-4 tail), or a CTLA-4
Tyr201 mutant (Y201V) were introduced into CTLA-4-deficient
mice. CTLA-4-/- mice display an autoimmune
lymphoproliferative disorder resulting in tissue destruction and early
death. When either the FL or the Y201V transgene was bred into
CTLA-4-/- animals, a complete rescue from
lymphoproliferation and autoimmunity was observed. In contrast,
CTLA-4-/- mice expressing the CTLA-4 tail transgene
were long lived with no evidence of multiorgan lymphocytic
infiltration, but exhibited lymphadenopathy and accumulated large
numbers of activated T cells. Furthermore, these animals displayed a
Th2-biased phenotype which conferred susceptibility to
Leishmania infection. These results indicate that the
inhibitory effect of CTLA-4 is mediated in part through the ability of
the extracellular domain to compete for ligands. The cytoplasmic domain
of CTLA-4, however, is required for complete inhibitory function of the
receptor and for regulation of Th cell differentiation in
vivo.
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