Transcriptional repressor BCL6 controls Th17 responses by controlling gene expression in both T cells and macrophages.
The transcriptional repressor protein BCL6 regulates T cell differentiation by repressing Th2 responses and promoting follicular Th cell responses. However, little is known about the role of BCL6 in Th17 responses. We found that memory T cells from BCL6-deficient mice had increased IL-17 production. Additionally, BCL6 expression is upregulated in CD4 T cells cultured under Th17 conditions. T cells from BCL6-deficient mice showed defective Th17 differentiation and enhanced IL-4 production in vitro; however, normal Th17 differentiation was obtained with BCL6-deficient T cells under culture conditions when highly pure naive CD4 T cells were used, when IL-4 production was inhibited, or when TGF-beta levels were increased. Retrovirus-mediated expression of BCL6 in CD4 T cells repressed IL-4 and augmented basal IL-17 mRNA expression. These data support the idea that BCL6 promotes Th17 differentiation through suppression of Th2 differentiation. BCL6-deficient T cells transplanted into Rag1(-/-) mice produced wild-type levels of IL-17, indicating that, in vivo, BCL6-deficient T cells develop relatively normal Th17 responses. Macrophages from BCL6-deficient mice showed strikingly increased expression of the Th17-promoting cytokines IL-6, IL-23, and TGF-beta, and conditioned media from BCL6-deficient macrophages promoted augmented IL-17 expression by T cells. We propose that the increased Th17 activity in BCL6-deficient mice is due, in part, to BCL6-deficient macrophages promoting increased Th17 differentiation in vivo. T cells may require BCL6 for optimal Th17 differentiation; however, BCL6 function in macrophages critically regulates Th17 differentiation in vivo. We hypothesize that increased Th17 differentiation aggravates the severe Th2-type inflammatory disease in BCL6-deficient mice.
Mondal
Arpita
A
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sawant
Deepali
D
Dent
Alexander L
AL
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics* / Q000276:immunology*; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C098680:Il17a protein, mouse; D020381:Interleukin-17; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins