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CTLA-4 engagement regulates NF-kappaB activation in vivo
Helena Harlin1, Kwang Woo Hwang, David A Palucki
1Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, Ill 60637 USA.
Abstract:
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.
Insights
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) engagement suppresses T cell responses by inhibiting NF-kappaB. Impairing NF-kappaB in CTLA-4 deficient mice ameliorates lymphoproliferative disorder, demonstrating CTLA-4
Area of Science:
- Immunology
- Molecular Biology
- Cellular Signaling
Background:
- Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key regulator of T cell activation.
- CTLA-4 engagement inhibits T cell receptor (TCR)-dependent functions.
- CTLA-4 deficiency leads to a lethal lymphoproliferative disorder.
Purpose of the Study:
- To investigate the role of NF-kappaB inhibition in CTLA-4-mediated T cell regulation in vivo.
- To determine if NF-kappaB is a necessary downstream target for CTLA-4's immunosuppressive function.
Main Methods:
- Generation of CTLA-4(-/-) mice with impaired NF-kappaB activity using a transdominant IkappaBalpha mutant.
- Analysis of T cell activation markers, cytokine production, mortality, and leukocytic infiltration in spleen, lymph nodes, and pancreas.
- Assessment of spontaneous NF-kappaB activity in T cells from genetically modified mice.
Main Results:
- Mice with impaired NF-kappaB activity and CTLA-4 deficiency exhibited reduced spontaneous NF-kappaB activity in T cells.
- These mice showed delayed mortality and decreased leukocytic accumulation compared to CTLA-4(-/-) littermates.
- Impaired NF-kappaB activation did not prevent T cell activation marker upregulation or effector cytokine production.
Conclusions:
- NF-kappaB inhibition is a critical mechanism by which CTLA-4 ligation regulates T cell responses in vivo.
- Targeting the NF-kappaB pathway downstream of CTLA-4 can mitigate the pathological consequences of CTLA-4 deficiency.
- CTLA-4's regulation of T cell survival and function involves modulation of NF-kappaB signaling.