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FRI0007 The transcription factor C-MAF plays an essential role in a memory TH-cell dependent model of inflammation

Background Th17 cells are a recently identified effector T-helper (Th) cell subset, which has been suggested to play an important role in various inflammatory diseases, and thus has gathered considerable attention. Indeed, antibodies to interleukin (IL-)17, a representative cytokine produced by Th17 cells, have been shown to have clinical efficacy against psoriatic arthritis and also are undergoing clinical trials for rheumatoid arthritis (1, 2). We reported in this meeting 2 years ago the following results: (i) The transcription factor c-Maf is highly expressed in Th17 cells. (ii) One of its transcriptional target is Il23r. (iii) Most of the Th cells in c-Maf transgenic mice have an effector-memory phenotype (3). Objectives The role c-Maf plays in memory Th cells is scarcely known. Thus, we aim to investigate it. Methods As c-Maf-deficient mice are embryonically lethal, it was necessary to make chimeras of T-cell deficient Rag-1 or 2 knockout mice and hematopoietic stem cells derived from c-Maf deficient embryos. We utilized a colitis model in which naïve Th cells were transferred into Rag knockout mice (4) and analyzed the role c-Maf played in vivo. We also sorted human Th cells into naïve, central memory and effector memory cells based on their surface markers, and performed transcriptome analysis to identify the expression pattern of the transcription factors in human naïve and memory Th cells. Results Rag-2 knockout mice that received Maf-/- naïve Th cells exhibited a lesser degree of colitis than control mice that received WT naïve Th cells. In human Th cells, the expression of MAF encoding c-MAF was the highest in effector memory cells and the lowest in naïve cells, demonstrating that the expression of MAF is induced in the course of differentiation from naïve to memory Th cells. Conclusions c-Maf plays an important role in the inflammation that is dependent on memory-phenotype Th cells. In human Th cells, too, c-MAF is strongly induced in memory Th cells, suggesting the importance of this transcription factor across species. Further study will be needed to elucidate its function in detail. References Genovese, M. C., et al.: Arthritis Rheum, 62: 929-939.2010. Hueber, W., et al.: Sci Transl Med, 2: 52ra72.2010. Sato, K., et al.: J Biol Chem, 286: 14963-14971.2011. Powrie, F., et al.: J Exp Med, 183: 2669-2674.1996. Disclosure of Interest None Declared