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A Critical Regulatory Role of Leucin Zipper Transcription Factor c-Maf in Th1-Mediated Experimental Colitis¹

Benno Weigmann^*, Andrea Nemetz^*, Christoph Becker^*, Jan Schmidt, Dennis Strand^*, Hans A. Lehr, Peter R. Galle^*, I.-Cheng Ho and Markus F. Neurath^2,*

^* Laboratory of Immunology, I. Medical Clinic, and Institute of Pathology, University of Mainz, Mainz, Germany; Harvard School of Public Health and Harvard Medical School, Boston, MA 02115; and Department of Surgery, University of Heidelberg, Heidelberg, Germany

In this study, we investigated the role of c-Maf, a transcription factor known to induce IL-4 production, in inflammatory bowel diseases and experimental colitis. Although Crohn's disease (CD) is associated with low IL-4 production by T-bet-expressing Th1 cells in the lamina propria, surprisingly a higher expression of c-Maf in these cells was found as compared with control patients. The relevance of this finding was further evaluated in an animal model of CD induced by adoptive transfer of CD4⁺CD62L⁺ T cells in RAG-deficient mice. In this Th1-mediated model, an increase of c-Maf-expressing T lymphocytes in the lamina propria over time was observed. Interestingly, adoptive transfer of c-Maf transgenic CD4⁺CD62L⁺ T cells in RAG-1-deficient mice resulted in an IL-4-dependent inability to induce colitis and suppressed colitis activity induced by wild-type CD4⁺CD62L⁺ T cells. In contrast, transfer of CD4⁺CD62L^– T cells from c-Maf transgenic, but not wild-type mice induced colitis and augmented colitis induced by CD4⁺CD62L⁺ T cells from wild-type mice in an IL-4-independent pathway, as determined by macroscopic, histologic, and endoscopic criteria. This was associated with an accumulation of CD4⁺ T-bet⁺ CD25⁺ effector Th1 cells in the lamina propria of colitic mice. Our results reveal a novel regulatory role of c-Maf in colitis. Although overexpression of c-Maf in naive T cells prevents Th1-mediated colitis, overexpression of c-Maf in memory T-bet⁺ Th1 cells regulates CD25 expression and augments such colitis. Targeting of c-Maf in memory T cells in CD appears to be an attractive target for therapeutic interventions.