title: Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor-transgenic CTLA-4-deficient mice.
abstract: CTLA-4 is a T cell surface receptor essential for the negative regulation of T cell activation. In the CTLA-4-deficient mouse, a dramatic accumulation of activated peripheral T cells effects extensive damage to host tissues, resulting in mortality within 5 weeks of age. To determine whether the accumulation of activated T cells in CTLA-4(-/-) mice is due to a defect in thymic selection, we examined negative selection in CTLA-4(-/-) mice using two transgenic T cell receptor (TCR) models of thymic selection. Neither the H-Y-specific TCR nor the lymphocytic choriomeningitis virus (LCMV)-specific TCR transgenic models revealed a defect in positive or negative selection in CTLA-4(-/-) mice in vivo or in vitro. In fact, the negatively selecting phenotype of male H-YTCR-transgenic mice greatly mitigated the accumulation of activated peripheral T cells. Further, peripheral CTLA-4(-/-) T cells expressing a single LMCV-specific transgenic TCR did not have an activated phenotype, indicating that CTLA-4(-/-) T cells require specific antigen for proliferation. These results demonstrate that specific antigen is required for the lymphoproliferation observed in CTLA-4(-/-) mice, and that CTLA-4 deficiency does not lead to a gross defect in negative selection.
authors.affiliation: Amgen Institute, Toronto, Ontario, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Waterhouse
authors.forename: M F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002470:Cell Survival / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006182:H-Y Antigen / Q000378:metabolism; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D006182:H-Y Antigen; D018796:Immunoconjugates; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept