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Bram Margry

Tuesday 18 March 2014

Bidirectional regulation between B cells and T cells

Promotor: Prof. dr W. van Eden
Defence: 18 March 2014

B cells were often thought of as simple precursors of end-stage effector cells that are merely in charge of antibody production. Research in the last decades has shown that B cells possess important other roles as well, including their involvement in the regulation and functioning of T cell-mediated (autoimmune) diseases and host-protective immune responses.

This thesis aimed to get a better understanding of the variety of roles B cell subsets play in immune regulation, and how the reciprocal interplay between B- and T cells shapes the outcome of an immune response. Knowledge on how specific B cell subsets influence other players of the immune network provides valuable information that can be used to develop and improve therapies aimed to restore the balance in dysregulated immune systems such as during autoimmunity.

Chapter 2 describes research investigating an experimental tolerogenic vaccination strategy. An immunodominant peptide of proteoglycan (PG) was recombinantly fused to a DEC205 endocytic receptor-specific antibody (anti-DEC205-PG). Administration of anti-DEC205-PG delivers PG-peptide to tolerogenic steady-state dendritic cells, and mice prophylactically treated with anti-DEC205-PG do not develop experimental arthritis. Our investigations showed that the DEC205-mediated tolerogenic vaccination resulted in a reduced availability of arthritic PG-specific (follicular) helper T-cells and (temporarily) increased numbers of FoxP3+ regulatory T cells. The amount of B cells participating in germinal centers was subsequently lower as well. Our data suggests that the reduced availability in germinal center-supporting follicular helper T cells eventually limits the production of autoantibodies required for the pathogenesis of arthritis.

Chapter 3 and 4 describe research in the immune-regulatory roles of murine peritoneal cavity-derived innate-like B- and B-1a cells when they act either as antigen-presenting cells (APCs) or secrete immunoregulatory cytokines. Chapter 3 shows that peritoneal cavity (PerC) B cells acting as APCs, when compared to splenic B cells, differently activate CD4+ helper T (Th) cells in vitro. Higher percentages of the Th cells activated by PerC B-1a cells possess the ability to secrete the cytokines interferon-γ (IFN-γ), interleukin (IL)-10 and IL-4. This new immunological pathway may be of relevance in vivo, since adoptive transfer experiments showed that peripheral Th cells could be activated locally in the PerC by B-1a cells.

Chapter 4 shows that activated PerC B cells produce large amounts of the anti-inflammatory cytokine IL-10. These activated PerC B cells can subsequently function as regulatory B cells (Bregs), since they reduce the amount of Th cells that can produce the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IFN-γ in an in vitro Breg-suppression assay. The activation status of PerC B cells turned out to be crucial in this matter, since non-activated PerC B cells increased the amount of TNF-α-producing Th cells instead.

Chapter 5 describes an investigation towards the B-cell epitopes on the G1 domain of the joint-derived self-antigen proteoglycan. Our research shows that both proteoglycan-induced arthritic mice and some rheumatoid arthritic patients possess certain antibodies directed against G1-specific B cell epitopes. This knowledge may be useful for the development of new diagnostic tools, e.g., to differentiate clinical subsets of arthritis patients.