MiT Family of Transcription Factors Regulates B cell Development and Immune Tolerance

Abstract

B cells are the sole producers of antibodies that are essential for protective immunity, but when directed against self cause severe autoimmune disease. In the current work, I analyzed the mechanism of regulation of B cell development, function, and tolerance to self by the MiT family of transcription factors by studying how their functional absence in mice affects these B cell properties. Previous studies on Mitf, a MiT member, suggested its importance for maintaining a sufficient threshold of B cell activation needed to curb benign autoantibody production. However, the experimental design of those studies left open the questions of to what extent this was B cell intrinsic and whether other MiT family members were involved. To address these issues, I developed new models of MiT family inactivation designed to reveal B lymphocyte-specific functions of the MiT family. Among these are transgenic mice that express in lymphocytes a recombinant trans dominant negative (TDN) protein that inhibits all MiT family proteins by forming inactive heterodimers. Additionally, I used mouse lines with genetic deficiencies in Mitf, TFE3 and/or TFEB. Using these complementary mouse genetic approaches of MiT family inactivation, I determined 1) that Marginal Zone B cells, critical for antibody responses against encapsulated bacteria, and peritoneal B-1a B cells, a major source of immunoregulatory natural IgM antibody, both depend on TFEB and TFE3; 2) that simultaneous inactivation of Mitf, TFE3, and TFEB in B cells leads to T helper dependent splenomegaly, follicular dysplasia, elevated spontaneous plasma cell development, elevated IgG, and benign autoantibody production, and that 3) MiT inactivation in B cells dramatically accelerates and exacerbates lupus-like autoimmune disease caused by the lpr Fas mutation. My studies reveal the critical importance of the MiT family and individual MiT members to B cell development and tolerance. These findings identify new pathways and possible therapeutic target candidates that may be used to control pathological B cell responses.