B cell-mediated CD4 T-cell costimulation via CD86 exacerbates pro-inflammatory cytokine production during autoimmune intestinal inflammation

Abstract

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for a detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as a mouse model of chronic colitis, we identified CD86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking co-stimulatory signals mediated by CD86 through CTLA-4-Ig diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially IFN-γ and GM-CSF. Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1-/- mice, we also found CD86 mRNA and protein expression up-regulated on activated B cells isolated from inflamed tissue of human IBD patients. B cell activation and CD86 expression was boosted by soluble CD40L in vitro, which we found in the serum of mice and human IBD patients. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.