Christoph Schwaerzler

Deficient translocation of c‐Rel is associated with impaired Th1 cytokine production in T cells from atopic dermatitis patients

Abstract:  Decreased production of T helper type 1 (Th1) cytokines, such as interferon‐γ (IFN‐γ) or interleukin‐2 (IL‐2), is a hallmark of atopic diseases. While accessory signals from antigen‐presenting cells may be missing, T cells themselves may be suppressed in their ability to produce substantial amounts of Th1 cytokines. We show, in this study, that T cell receptor (TCR)‐activated T cells from atopic dermatitis (AD) patients proliferate less than control T cells and produce lower amounts of IFN‐γ and IL‐2, but comparable amounts of IL‐4. Because mice lacking the nuclear factor kappa B (NF‐κB) transcription factors – p65 or c‐Rel – show reduced Th1, but undisturbed Th2 responses, we investigated the role of c‐Rel and p65 for Th1 cytokine production in T cells from healthy and severe AD patients. TCR‐activated primary T cells from healthy donors treated with c‐Rel antisense oligonucleotides produced lower levels of IL‐2 and IFN‐γ and proliferated less efficiently than the corresponding control T cells. Moreover, transfection of primary T cells with c‐Rel or p65 enhanced proliferation and production of IL‐2 and IFN‐γ. Nuclear extracts of activated primary T cells from AD donors bound weakly to NF‐κB‐specific oligonucleotides, compared to extracts from healthy control T cells. Western blotting studies revealed that nuclear, but not cytosolic, extracts from T cells of AD patients lacked significant amounts of c‐Rel and p65. T cell clones derived from AD patients failed to sufficiently translocate c‐Rel and p65 into the nucleus following activation. Thus, impaired nuclear translocation of c‐Rel and p65 may determine an impaired Th1 cytokine response in AD.