CTLA-4 engagement regulates NF-kappaB activation in vivo.

Harlin H, Hwang KW, Palucki DA, Kim O, Thompson CB, Boothby M, Alegre ML
Eur J Immunol. 2002 32 (8): 2095-104

PMID: 12209621 · 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.

MeSH Terms (17)

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

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