NF-kappaB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells.

Baochun Zhang,Han-Fei Ding,William T Gunning,Jane Ding,Zhe Wang,Pärt Peterson

doi:10.1074/jbc.m606705200

Abstract

Medullary thymic epithelial cells function as antigen-presenting cells in negative selection of self-reactive T cell clones, a process essential for the establishment of central self-tolerance. These cells mirror peripheral tissues through promiscuous expression of a diverse set of tissue-restricted self-antigens. The genes and signaling pathways that regulate the development of medullary thymic epithelial cells are not fully understood. Here we show that mice deficient in NF-kappaB2, a member of the NF-kappaB family, display a marked reduction in the number of mature medullary thymic epithelial cells that express CD80 and bind the lectin Ulex europaeus agglutinin-1, leading to a significant decrease in the extent of promiscuous gene expression in the thymus of NF-kappaB2(-/-) mice. Moreover, NF-kappaB2(-/-) mice manifest autoimmunity characterized by multiorgan infiltration of activated T cells and high levels of autoantibodies to multiple organs. A subpopulation of the mice also develops immune complex glomerulonephritis. These findings identify a physiological function of NF-kappaB2 in the development of medullary thymic epithelial cells and, thus, the control of self-tolerance induction.

Highlights

Trum of peripheral tissue-restricted self-antigens, termed promiscuous gene expression [5, 6]
It was recently suggested that it is the increase in the p100 levels, rather than the absence of p52, that might be responsible for the impaired medullary thymic epithelial cells (mTECs) development observed in IKK␣-deficient and NIKaly/aly mice [24]
In this report we describe an autoimmune phenotype for NF-␬B2Ϫ/Ϫ mice, manifesting as multiorgan infiltration of activated T cells, high levels of autoantibodies in the serum, and spontaneous development of immune complex glomerulonephritis in a subpopulation of the mice

Summary

Introduction

Trum of peripheral tissue-restricted self-antigens, termed promiscuous gene expression [5, 6]. Cryostat sections of various organs from 8-week-old NOD.SCID/NCr mice were fixed in cold methanol for 5 min, blocked with 10% goat serum in PBS for 1 h at room temperature, and incubated with 1:40 dilutions of the serum from individual 1-year-old NF-␬B2Ϫ/Ϫ and wild-type littermates.

Results

Conclusion