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Structural analysis of CTLA-4 function in vivo
E L Masteller1, E Chuang, A C Mullen
1Gwen Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA. emastell@delphi.bsd.uchicago.edu
Abstract:
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 (DeltaCTLA-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 DeltaCTLA-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.
Insights
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibits T cell activation. Its extracellular domain competes for ligands, while the intracellular domain regulates T cell differentiation and receptor function.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is crucial for T cell regulation.
- CTLA-4's intracellular domain, particularly Tyr201, influences its signaling and trafficking.
- CTLA-4 deficiency in mice leads to autoimmune lymphoproliferative disorder.
Purpose of the Study:
- To investigate the in vivo mechanisms of CTLA-4 function.
- To determine the roles of CTLA-4's extracellular and intracellular domains in immune regulation.
Main Methods:
- Generation of CTLA-4-deficient mice expressing transgenes for wild-type CTLA-4 (FL), CTLA-4 lacking the cytoplasmic tail (DeltaCTLA-4 tail), or a Tyr201 mutant (Y201V).
- Assessment of immune phenotypes, including lymphoproliferation, autoimmunity, T cell activation, and Th cell differentiation.
Main Results:
- FL and Y201V transgenes rescued CTLA-4-/- mice from autoimmunity and lymphoproliferation.
- DeltaCTLA-4 tail transgene expression prevented lethality but resulted in lymphadenopathy and activated T cells.
- Mice with DeltaCTLA-4 tail exhibited a Th2-biased phenotype and susceptibility to Leishmania infection.
Conclusions:
- CTLA-4's extracellular domain contributes to inhibition by ligand competition.
- The intracellular domain of CTLA-4 is essential for full inhibitory function and regulation of Th cell differentiation.
- CTLA-4 signaling and ligand binding are critical for maintaining immune homeostasis.