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

Crohn's disease pathology is modeled in TNF^ΔARE+/- mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα₃, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ₂ that promotes tertiary lymphoid tissue-another feature of Crohn's disease. We hypothesized that B cell-derived LTαβ₂ would critically affect ileitis in TNF^ΔARE+/- mice. 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 IgA⁺ ileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass-a systemic feature of Crohn's disease. Neutralizing antibodies to LTα₃ strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ₂ and LTα₃ have distinct roles in ileitis, with the role of LTα₃ unexpectedly protective through counterbalancing TNF.