Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance

• DOI: 10.3389/fimmu.2024.1339325
• Publication Date: 2024-02-20T05:46:20Z
• Authors: Abhimanyu Amarnani; Maria Lopez-Ocasio; Ramile Dilshat; Kamala Anumukonda; Jonathan Davila; Nikita Malakhov; Chongmin Huan; Erna Magnusdottir; Eirikur Steingrim...; Christopher A. Roman
• Keywords: Microphthalmia-associated transcription factor; IRF4

Introduction The microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying cell-specific mechanisms responsible, those that distinguish from closely related Mitf/TFE (MiT) factors Tfe3, Tfeb, Tfec, remain obscure. Methods Two complementary mouse models of MiT deficiency were used: mi-vga9/mi-vga9 systemic loss-of-function mutation, B-cell specific family inactivation via transgenic expression a trans-dominant negative (TDN) protein (TDN-B). These employed identify candidate target genes pathways. Results Both displayed spontaneous splenomegaly coincident with elevated plasma numbers, autoantibody titers, proteinuria. abnormalities appeared dependent on T helper cells, but independent other non-B intrinsic effects inactivation. in cells augmented aspects lupus-like autoimmune disease C57BL/6-Fas lpr/lpr background. In both models, RNAseq ex vivo resting showed transcriptional upregulation control cycle, germinal center responses, differentiation. Among strongly upregulated Socs6, Isp53 (Baiap1), S1pR2, IgG2b/c. null not TDN-B evidence type I interferon dysregulation. Discussion studies clarify Mitf’s role as 1) key regulator program influences self-tolerance through novel genes, 2) inflammatory processes can impact microenvironment. This distinction Mitf's function advances our understanding regulation autoimmunity.