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Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.

Immunity | Nov 26, 1995

The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.

Pubmed ID: 7584144 RIS Download

Mesh terms: Abatacept | Animals | Antigens, CD | Antigens, Differentiation | Base Sequence | CTLA-4 Antigen | Cells, Cultured | Cytokines | DNA Primers | Down-Regulation | Immunoconjugates | Immunohistochemistry | Lymphocyte Activation | Lymphoid Tissue | Lymphoproliferative Disorders | Mice | Mice, Mutant Strains | Mice, Transgenic | Molecular Sequence Data | T-Lymphocytes | Viscera

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Associated grants

  • Agency: NIAMS NIH HHS, Id: 1P30AR42689
  • Agency: NIAID NIH HHS, Id: P01 AI35225
  • Agency: NHLBI NIH HHS, Id: T32HLO7627

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