ABSTRACT
The function of NF-κB family members is controlled by multiple mechanisms including the transcriptional regulator Bcl-3, an atypical member of the IκB family. By using a murine model of conditional Bcl-3 overexpression specifically in T cells, we observed impairment in the development of Th2, Th1, and Th17 cells. High expression of Bcl-3 promoted CD4+ T-cell survival, but at the same time suppressed proliferation in response to TCR stimulation, resulting in reduced CD4+ T-cell expansion. As a consequence, T-cell-specific overexpression of Bcl-3 led to reduced inflammation in the small intestine of mice applied with anti-CD3 in a model of gut inflammation. Moreover, impaired Th17-cell development resulted in the resistance of Bcl-3 overexpressing mice to EAE, a mouse model of multiple sclerosis. Thus, we concluded that fine-tuning expression of Bcl-3 is needed for proper CD4+ T-cell development and is required to sustain Th17-cell mediated pathology.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Proto-Oncogene Proteins/genetics , Th17 Cells/immunology , Transcription Factors/genetics , Animals , B-Cell Lymphoma 3 Protein , CD3 Complex/immunology , Cell Differentiation , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Inflammation , Intestine, Small/immunology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins/metabolism , Th1 Cells/immunology , Th2 Cells/immunology , Transcription Factors/metabolismABSTRACT
Interleukin-1 (IL-1) is implicated in numerous pathologies, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which IL-1 is involved in the generation of pathogenic T cells and in disease development remains largely unknown. We found that following EAE induction, pertussis toxin administration leads to IL-1 receptor type 1 (IL-1R1)-dependent IL-1ß expression by myeloid cells in the draining lymph nodes. This myeloid-derived IL-1ß did not vitally contribute to the generation and plasticity of Th17 cells, but rather promoted the expansion of a GM-CSF+ Th17 cell subset, thereby enhancing its encephalitogenic potential. Lack of expansion of GM-CSF-producing Th17 cells led to ameliorated disease in mice deficient for IL-1R1 specifically in T cells. Importantly, pathogenicity of IL-1R1-deficient T cells was fully restored by IL-23 polarization and expansion in vitro Therefore, our data demonstrate that IL-1 functions as a mitogenic mediator of encephalitogenic Th17 cells rather than qualitative inducer of their generation.
