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B cell-intrinsic functions of the MALT1 paracaspase

  • Author(s): Lee, Peishan
  • Advisor(s): Rickert, Robert
  • Bui, Jack
  • et al.
Abstract

During a T cell-dependent immune response, formation of the germinal center (GC) is essential for the generation of high-affinity plasma cells and memory B cells. The canonical NF-κB pathway has been implicated in the initiation of GC reactions and defects in this pathway have been linked to immune deficiencies. The paracaspase MALT1 plays an important role in regulating NF-κB activation upon triggering of antigen receptors. Although previous studies have reported that MALT1 deficiency abrogates the GC response, the relative contribution of B cells and T cells to the defective phenotype remains unclear.

To this end, I utilized chimeric mouse models to demonstrate that there is a B cell-intrinsic requirement for MALT1 in the initiation of GC response. In Chapter 2, I show that MALT1 is critical for proliferation and survival of B cells in response to signaling specifically through the B cell receptor, which cannot be overcome by providing T cell help. In addition to the GC defect, MALT1-deficient B cells were impaired in differentiation to plasma cells, although proliferation to mitogens was unaffected. In Chapter 3, I show that in the presence of normal T cells, ectopic expression of Bcl-2 in MALT1-deficient B cells can partially rescue the GC phenotype by prolonging the lifespan of activated B cells, but plasma cell differentiation and antibody production remain defective. Chapter 4 presents work on the regulation of MALT1 proteolytic activity in B cells, including the application of the activity-based probe to monitor MALT1 activity in situ and exploration of mechanisms leading to induction of MALT1-mediated proteolysis. Collectively, the findings described in this dissertation uncover a previously underappreciated role of MALT1 in B cells and highlight its importance in humoral immunity.

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