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N-Acetyl-L-Cysteine Inhibits Primary Human T Cell Responses at the Dendritic Cell Level: Association with NF-B Inhibition¹

Valérie Verhasselt^*, Wim Vanden Berghe, Nathalie Vanderheyde^*, Fabienne Willems^*, Guy Haegeman and Michel Goldman^2,*

^* Laboratory of Experimental Immunology and Centre de Recherche Interuniversitaire en Vaccinologie, Université Libre de Bruxelles, Brussels, Belgium; and Department of Molecular Biology and Flanders Interuniversity Institute for Biotechnology, University of Gent, Belgium

N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-B. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.