Loss of CTLA-4 Leads to Massive Lymphoproliferation and Fatal Multiorgan Tissue Destruction, Revealing a Critical Negative Regulatory Role of CTLA-4

Immunity. 1995 Nov;3(5):541-7. doi: 10.1016/1074-7613(95)90125-6.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / physiology*
  • Base Sequence
  • CTLA-4 Antigen
  • Cells, Cultured
  • Cytokines / biosynthesis
  • DNA Primers / chemistry
  • Down-Regulation / genetics
  • Immunoconjugates*
  • Immunohistochemistry
  • Lymphocyte Activation / genetics
  • Lymphoid Tissue / pathology*
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / mortality
  • Lymphoproliferative Disorders / pathology*
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Molecular Sequence Data
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Viscera / pathology*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Cytokines
  • DNA Primers
  • Immunoconjugates
  • Abatacept