CD86 Signaling in B Cells

Sanders, Virginia

Abstract

CD86 (B7-2) on a B cell recognizes CD28 and promotes T cell activation. Recent data show that CD86 may also mediate signals directly to a B cell to modulate the level of IgG1/IgG4 produced, without affecting class switch recombination. The overall goal of this research project is to identify the mechanism by which CD86 on a murine or human B cell promotes an increase in an Ab isotype that neutralizes infectious organisms such as Streptococcus pneumoniae. Using a murine adoptive transfer model with CD86- deficient B cells, we showed that these B cells were unable to produce a control level of pneumococcal polysaccharide-specific IgG1 or IgG3 when compared to wildtype B cells, suggesting a potential physiologic role for CD86 in modulating the level of protective antibody produced by a B cell. CD86 stimulation on a CD40L/IL-4-activated primary B cell in vitro was found to increase PI3K activity, with CD19 serving as a potential link between these events. We recently found that the B cell receptor-associated protein-37 (BAP37), but not CD19, immunoprecipitated with CD86 from the CH12.LX B cell line, and that phosphoserine/threonine deletions within the CD86 cytoplasmic domain failed to disrupt BAP37 association with CD86, but diminished CD86-induced function without affecting CD40L/IL-4 function. Collectively, these data challenge the accepted dogma that CD86 is only a recognition molecule for CD28, and emphasizes the need to better understand proximal signaling mechanisms and strengthen physiological relevance. We propose to test the hypothesis that CD86 stimulation on a B cell facilitates the activation of signaling intermediates that promote an increase in the level of IgG1. Proposed experiments will determine if a signaling intermediate is recruited/activated by CD86 stimulation to facilitate signaling function, if specific domains of CD86 and the membrane microenvironment play a role in CD86 function, and if there is functional and physiological relevance for CD86 recognition vs. signaling. The significance of testing our hypothesis is that a unique function for CD86, as well as molecular targets for therapeutics, will be identified to alleviate deficiencies in IgG1/ IgG4-mediated protection against infectious organisms such as S. pneumoniae, a leading cause of death in individuals with cancer.