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Balanced Bcl-3 expression in murine CD4(+) Tcells is required for generation of encephalitogenic Th17 cells

Mufazalov, IA;Kuschmann, J;Andruszewski, D;Masri, J;Gabriel, LA;Adams, P;Reissig, S;Hvelmeyer, N;Waisman, A;

The function of NF-B family members is controlled by multiple mechanisms including the transcriptional regulator Bcl-3, an atypical member of the IB 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.