B cells as antigen-presenting cells in a model of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a multifaceted inflammatory autoimmune disease characterised by the infiltration of leukocytes into synovial joints leading to the destruction of articular cartilage and bone. Autoreactive CD4+ T cells producing inflammatory cytokines are implicated in disease pathogenesis. The clinical efficacy of B cell-depletion therapy is not dependent on clearance of autoantibodies suggesting a critical role for B cells as antigen presenting cells (APC). To elucidate the role of B cells in activating CD4+ T cells in RA, this project examined B cell- mediated antigen presentation to CD4+ T cells isolated from T cell receptor (TCR)-transgenic mice specific for the major arthritogenic epitope of the candidate cartilage autoantigen, aggrecan. This system allows for direct comparison of aggrecan-specific B cells to dendritic cells (DC) and other APC in order to identify any unique consequences of B cell antigen presentation and modulation of CD4+ T cell effector cytokine production. The data presented here show the activation, proliferation and effector function of CD4 T cells co- cultured with different APC in the presence of aggrecan and demonstrate key differences in B cell and DC production of disease-relevant cytokines. Crucially, aggrecan-specific B cells induced greater CD4+ T cell production of the pathogenic cytokine IFN-γ than DC, despite equivalent IL-2 production. The role of aggrecan-mediated activation of several pattern recognition receptors in this process was excluded using an in vitro detection system. However, the identification of a differential requirement for CD80 and CD86 during antigen presentation by B cells and DC suggested a role for co-stimulatory molecules at the APC-T cell interface in mediating B cell induction in CD4 T cell IFN-γ production. In summary, this work highlights the role of the CD80/86-CD28 pathway in mediating the observed differential induction of CD4+ T cell IFN-γ production by antigen-specific B cells and DC following aggrecan presentation.