Identification of structural modules within the transcription factor IRF4 controlling T helper cell subtype diversification

• Applicant: Professor Dr. Michael Lohoff
• Subject Area: Immunology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318273838

As our many years of preliminary work show, the transcription factor (TF) IRF4 is crucially involved in the differentiation of different subtypes of T helper cells. In a division of labour, their physiological function lies in the regulation of different immune pathways in the organism, for example in the defense against extracellular bacteria (Th17), intracellular viruses (Th1) or worms (Th2, Th9). On the other hand, an imbalance in these subtypes leads to diseases such as multiple sclerosis, asthma or colitis. In contrast to IRF4, there are other TFs that are specific and essential for each of the subtypes (such as GATA3, STAT6, PU.1 or RORgT). Loss of such a TF leads to selective resistance to the disease mediated by the particular T cell subtype. IRF4 is known to physically interact with these other TFs. We therefore hypothesize that structural and functional modules of IRF4 exist which each bind to only one of the other TFs and thus specifically contribute to its individual function. Such modules should be identifiable by IRF4 mutants in which only partial functions are selectively lost. In the first funding period, we generated and partially characterized 40 mutants of IRF4. We have succeeded in describing two mutations with partial functions. In the first, there is hyperactivity of IRF4, mainly increasing Th17 function, while in the other, Th9 is increased and Th17 is completely suppressed. In the present project we would first like to further characterize the 40 mutants. Furthermore, we want to analyze the mentioned two mutants in much greater depth by a) generating mice with these mutations, b) analyzing the immune cell phenotypes in these mice, c) analyzing the course of the mentioned diseases in these mice d) the analysis of those other TFs that physically interact with the respective mutants and are therefore co-precipitable, e) the clarification of the respective change in IRF4 structure by the mutation and f) use of this information for the identification of small molecule inhibitors, which provoke a similar loss of function in T cells with unmutated IRF4 and therefore presumably bind to the respective module. In the future, such inhibitors should be evaluated as therapeutic agents for the diseases mentioned.

• DFG Programme: Research Grants