RT Journal Article
SR Electronic
T1 Structural Analysis of CTLA-4 Function In Vivo
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 5319
OP 5327
DO 10.4049/jimmunol.164.10.5319
VO 164
IS 10
A1 Masteller, Emma L.
A1 Chuang, Ellen
A1 Mullen, Alan C.
A1 Reiner, Steve L.
A1 Thompson, Craig B.
YR 2000
UL http://www.jimmunol.org/content/164/10/5319.abstract
AB 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 (ΔCTLA-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 ΔCTLA-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.