Distinct roles for B cell-derived LTα3 and LTα1β2 in TNF-mediated ileitis.

Abstract

Crohn's disease pathology is modeled in TNFmice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβthat promotes tertiary lymphoid tissue-another feature of Crohn's disease. We hypothesized that B cell-derived LTαβwould critically affect ileitis in TNFmice. However, whereas deleting LTβ in B cells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of B cell-derived LTα increased intestinal permeability, shrunk the pool of IgAileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass-a systemic feature of Crohn's disease. Neutralizing antibodies to LTαstrongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβand LTαhave distinct roles in ileitis, with the role of LTαunexpectedly protective through counterbalancing TNF.