Induction mechanisms of B cell self-toleranace

点击翻译按钮获取中文摘要

We investigated the induction mechanisms of apoptosisi of self-reactive B cells developed in germinal centers using transgenic system. We show that1. The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, encodes a sequence-specific transcriptional repressor, and is strongly expressed in germinal center B and T cells. Adoptive transfer experiments with bone marrow cells from Bcl6-deficient (Bcl6-/-) mice revealed that Bcl6 is essential for the differentiation of germinal center B cells. Bcl6 was also detected in testicular germ cells, mainly spermatocytes, of normal mice. We found numerous apoptotic spermatocytes at the metaphase I stage with induction of Bax protein in adult Bcl6-/-testes. The incidence of apoptosis in heterozygous Bcl6+/-mice was also higher than that of Bcl6+/+mice. Since the activated form of p38 MAP kinase was detected in spermatocytes of adult Bcl6-/-mice, Bcl6 may play a role as a stabilizer in protecting spermatocytes from apoptosis induced by stresses.2. Bcl6-/-mice displayed massive eosinophilic inflammation. We have recently established transgenic mice carrying the Ig-Bcl6 or the lck-Bcl6 gene, and analyzed functions of lymphocytes of these Bcl6 transgenic mice. The germinal center fromation and memory responses were augmented in transgenic mice, suggesting that Bcl6 may play a role in survival of germinal center B cells.3. we describe a newly defined murine inhibitor of apoptosis (LAP), designated TIAP.TIAP interacted with the processed form of Caspase-3 and inhibited caspase-induced cell death. The expression of TIAP was upregulated in synchronized NIH3T3 cells at S to G2/M phase of the cell cycle. We propose that during cell proliferation, cellular protective activity may be augmented with inducible IAPs such as TIAP.We are investigating the role of TIAP in germinal center B cells.