Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation

• Published in: The Journal of cell biology Vol. 216; no. 3; pp. 779 - 792
• Main Authors: Vander Lugt, Bryan, Riddell, Jeremy, Khan, Aly A, Hackney, Jason A, Lesch, Justin, DeVoss, Jason, Weirauch, Matthew T, Singh, Harinder, Mellman, Ira
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 06.03.2017; The Rockefeller University Press
• Subjects: Animals; Antigen Presentation - genetics; Antigen Presentation - immunology; Antigens; Cell Differentiation - genetics; Cell Differentiation - immunology; Chromatin; Cytokines; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - physiology; Gene expression; Immune Tolerance - genetics; Immune Tolerance - immunology; Immune Tolerance - physiology; Interferon Regulatory Factors - metabolism; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; T cell receptors; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - physiology; Transcription, Genetic - genetics; Transcription, Genetic - immunology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201512012

Dendritic cells (DCs) promote either tolerogenic or immunogenic T cell responses, the latter upon sensing microbes. Using an in vitro system, we analyzed transcriptional determinants that enable mature DCs to direct these opposing T cell outcomes. In the absence of microbial products, the transcription factor interferon regulatory factor 4 (IRF4) promotes regulatory T cell (T ) generation by enhancing expression of genes required for antigen presentation along with those for T cell tolerance. IRF4-deficient DCs were impaired for T generation in vivo. When exposed to microbial stimuli, DCs activated nuclear factor (NF)-κB, which induced expression of a proinflammatory cytokine module that, along with the antigen presentation module, promoted the generation of effector T cells. NF-κB was, however, dispensable for T development. Chromatin profiling revealed transcriptional motifs associated with the divergent DC programs. Thus, DCs modulate their ability to prime tolerogenic or immunogenic T cells by expressing a core antigen presentation module that is overlaid by distinctive regulatory modules to promote either tolerance or immunity.