Costimulation reverses the defect in IL-2 but not effector cytokine production by T cells with impaired IkappaBalpha degradation.

Aune TM, Mora AL, Kim S, Boothby M, Lichtman AH
J Immunol. 1999 162 (10): 5805-12

PMID: 10229814

Although the transcriptional basis for states of unresponsiveness in primary T cells is unclear, tolerant B lymphocytes exhibit inhibition of both c-Jun N-terminal kinase induction and IkappaBalpha (inhibitor of NF-kappaBalpha) degradation, leading to lower levels of both nuclear AP-1 and NF-kappaB. Expression of an IkappaBalpha mutant resistant to signal-induced degradation in transgenic T cells caused markedly deficient effector cytokine (IL-4, IFN-gamma) production after primary TCR stimulation despite a detectable level of nuclear NF-kappaB. A TCR response element from the IFN-gamma promoter, despite lacking detectable NF-kappaB/Rel sites, was also unresponsive to TCR ligation. Nuclear induction of AP-1 proteins in response to T cell activation was diminished in transgenic T cells. Costimulation induced by anti-CD28 mAb increased IL-2 production, but failed to reverse the defects in effector cytokine production. Taken together, these data indicate that impaired NF-kappaB/Rel signaling in T cells interferes with the signal transduction pathways required for efficient induction of effector cytokine production.

MeSH Terms (21)

Animals CD4-Positive T-Lymphocytes CD28 Antigens Cytokines DNA-Binding Proteins I-kappa B Proteins Interferon-gamma Interleukin-2 Interleukin-4 Mice Mice, Mutant Strains Mice, Transgenic Mutation NF-kappa B NF-KappaB Inhibitor alpha Proto-Oncogene Proteins Proto-Oncogene Proteins c-rel Receptor Aggregation Receptors, Antigen, T-Cell Response Elements Signal Transduction

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