Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation

Bryan Vander Lugt,Jason A Hackney,Matthew T Weirauch,Ira Mellman,Jason Devoss,Justin Lesch,Harinder Singh,Jeremy Riddell,Aly A Khan

doi:10.1083/jcb.201512012

Bryan Vander Lugt, Jason A Hackney + Show 7 more

Open Access

https://doi.org/10.1083/jcb.201512012

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Abstract

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 (Treg) generation by enhancing expression of genes required for antigen presentation along with those for T cell tolerance. IRF4-deficient DCs were impaired for Treg 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 Treg 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.

Highlights

Dendritic cells (DCs) present peptide antigens to T cells and deliver important secondary signals that shape ensuing immune responses (Mellman and Steinman, 2001)
We recently described use of a bone marrow–derived dendritic cell (BMDC) culture system to analyze the functions of transcription factors interferon regulatory factor 4 (IRF4) and IRF8 in regulating DC maturation as well as major histocompatibility complex class II (MHCII) antigen presentation and priming of helper T cell (Th) responses
We demonstrated that both transcription factors (TFs) promoted DC maturation, but IRF4 preferentially enhanced expression of genes involved in MHCII antigen processing and presentation, thereby enabling more efficient priming of Th responses

Summary

Introduction

Dendritic cells (DCs) present peptide antigens to T cells and deliver important secondary signals that shape ensuing immune responses (Mellman and Steinman, 2001). Pathogenor inflammation-associated products license DCs to promote the differentiation of T cells into diverse effector states (Teff) that are tailored to effectively counter the infecting agent (Joffre et al, 2009) Such danger cues trigger dramatic alterations in DC organization and function, including enhanced antigen processing and surface display of peptide major histocompatibility complex class II (MHCII) complexes, induced expression of costimulatory molecules, and production of inflammatory cytokines necessary for Teff polarization (Trombetta and Mellman, 2005). In the steady state (the absence of infection or danger), DCs foster immune tolerance to self and innocuous environmental antigens (Steinman et al, 2003) This is accomplished in part by promoting the differentiation of naive T cells into immunosuppressive regulatory T cells (Treg). The findings imply that, depending on the signals received during maturation, DCs can manifest distinctive states with tolerogenic or immunogenic potential

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