CTLA-4 engagement regulates NF-kappaB activation in vivo

Eur J Immunol. 2002 Aug;32(8):2095-104. doi: 10.1002/1521-4141(200208)32:8<2095::AID-IMMU2095>3.0.CO;2-E.


CTLA-4 engagement inhibits TCR-dependent functions and CTLA-4(-/-) mice develop a lymphoproliferative disorder leading to early lethality. In vitro, ligation of CTLA-4 reduces TCR-mediated activation of NF-kappaB, a transcription factor implicated in promoting T cell survival and cytokine production. However, whether NF-kappaB inhibition downstream of CTLA-4 is necessary for down-regulation of T cell responses is not known. We hypothesized that signaling pathways that are antagonized when CTLA-4 is engaged should be augmented when CTLA-4 is absent and found thatspontaneous NF-kappaB activity was increased in T cells from CTLA-4(-/-) mice. To determine the importance of NF-kappaB inhibition upon CTLA-4 engagement in vivo, CTLA-4(-/-) mice were interbred with mice expressing a transdominant IkappaBalpha mutant under the control of the Lck promoter. The resulting mice had reduced spontaneous NF-kappaB activity in T cells,delayed mortality, and reduced leukocytic accumulation in spleen, lymph nodes, and exocrine pancreas as compared with CTLA-4(-/-) littermates. However, impaired NF-kappaB activation in T cells did not prevent the up-regulation of activation markers on T cells or the acquisition of effector cytokine production. Thus, impaired NF-kappaB activity in T cells prevents specific aspects of the CTLA-4(-/-) phenotype, suggesting that inhibition of NF-kappaB activation is one of the key biochemical events regulated by CTLA-4 ligation in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / physiology*
  • CTLA-4 Antigen
  • DNA-Binding Proteins / genetics
  • I-kappa B Proteins*
  • Immunoconjugates*
  • Interleukin-2 / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Pancreas / pathology
  • T-Lymphocytes / metabolism
  • Transgenes


  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Immunoconjugates
  • Interleukin-2
  • NF-kappa B
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha
  • Abatacept