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

All of these results indicate that T cells from CTLA4 -I- mice are activated in vivo, in the absence of overt stimulation by administered antigens

Elizabeth A. Tivol; Frank Borriello; A.Nicola Schweitzer; William P. Lynch; Jeffrey A. Bluestone; Arlene H. Sharpe


Scholarcy highlights

  • The importance of the B7-CD28/CTLA4 pathway in vivo has been illustrated dramatically by studies indicating that blockade of this pathway can induce long-term graft survival and suppress autoimmunity in rodents
  • Binding studies using a soluble form of CTLA4 or CD28, comprised of the extracellular domain of CTLA4 or CD28 and Fc portion of immunoglobulin G, indicate that CTLA4 can bind both 87-l and 87-2 with a lo- to 20-fold higher affinity than CD28
  • Our targeting vector replaced sequences encoding the IgV-like exon and a portion of the transmembrane exon of CTLA4 with the neomycin drug resistance gene, which should effectively destroy CTLA-4 binding to 67-l and 87-2
  • Germline-transmitting chimeric mice generated from targeted embryonic stem cells were bred to C57BU6 or BALBlc mice and progeny heterozygous for the CTLA4 mutation were interbred
  • CTLA4 deficiency resulted in a lethal phenotype, with death occurring by approximately 3-4 weeks of age
  • Our findings further suggest that the use of CTLA-4lg to block B7-mediated T cell activation may be complex, since CTLA-4lg could block both CD28-mediated costimulation and CTLA4-mediated inhibitory effects
  • In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury

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