B6: Role of interferon regulated factor (IRF) 4 for Th17 differentiation
CD4+ T cells can be classified into Th1- Th2-, Th17- and regulatory T (Treg) cells accor­ding to their specific cytokine profile upon stimulation (see also corresponding figure). During differentiation from naive CD4+ cells to the different subgroups, cytokine-in­duced specific transcription factors play a domi­nant role. Our group was the first one who could demonstrate that Interferon-regulator-factor (IRF) transcription factors are res­ponsible for the formation of the different T cell subtypes. IRF1 and IRF2 are impor­tant for Th1 differentiation and play also a domi­nant role during murine leish­ma­ni­osis. IRF4 was identified as the ‚master-trans­cription factor’ for Th2 develop­ment and its absence is associated with a dramatically enhanced activation-induced cell death (AICD). IRF4 is the central trans­cription factor not only for Th2- but also for Th17-differentiation with significance also for the development of experimental autoimmune encephalomyelitis (EAE), the murine disease model for multiple sclerosis (MS).

Project description

Beside STAT3 and RORγt, IRF4 is the central transcription factor for Th17 differenti­a­tion, albeit IRF4 is expressed by all CD4+ subtypes upon T-cell activation. IRF4-expres­sion by itself is therefore not sufficient to direct T-cell differentiation into a particular sub­type, but additional IRF4-binding-‚partners’ are necessary and/or modifi­ca­tions at the transcription factor itself. A still open question is also how IRF4 induces Th17 differentiation in the presence of TGF-ß plus IL-6, but does not play any role for Treg differention in the pre­sence of TGF-ß alone.
The central question to be answered in our project is therefore to specify the role of IRF4 during Th17 differentiation. Chromatin precipitation of IRF4 and ChIP-Seq tech­nique will allow to define IRF4-binding sites genomewide.
Further we will also analyse the impact of the different transcription factors and their mutual interaction during T cell differentiation at different time points. For this we will establish an inducible retroviral Tet-On-system. Hereby we will able to answer the following question:
  • how do the different transcription factors interact
  • at what time point do they interact
  • which are the critical time points during T cell subgroup differentiation
Our findings will also allow to analyse the significance of the tumor microenvironment on the generation of T cell subpopulations with pro- and/or anti-tumoral properties.


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Last Updated on Monday, 07 December 2009 16:16