Low levels of NF-κB/p65 mark anergic CD4+ T cells and correlate with disease severity in sarcoidosis

T lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-κB (p50, p65, and p105), IκBα (inhibitor of NF-κB), T-cell receptor (TCR) CD3ζ-chain, tyrosine kinase p56(LCK), and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4(+) T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4(+) T cells concurred with decreased levels of p50, p105, CD3ζ, p56(LCK), IκBα, and NF-ATc2. Polyclonal stimulation of NF-κB-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-γ]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.