Nonredundant Function of Soluble LTα ₃ Produced by Innate Lymphoid Cells in Intestinal Homeostasis

Abstract

Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt(+) innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt(+) ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt(+) cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.

Conditional Deletion of NF-κB–Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation

“…Peyer's patches in the gut are major sources of IgA production (65), and their integrity is maintained by LTbR signaling, possibly in a NIK-dependent manner (66,67). Consistent with this, we observed modest reductions in the number and cellularity of Peyer's patches following acute NIK deletion in vivo (data not shown).…”

Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor

“…It was also shown that TNFR1 has no unique specific ligand and may interact specifically with LT-␣, the closest homolog of TNF-␣. This cytokine may act differently with the receptor in the membrane-bound and the soluble form and highly affects IgA production (35). In this study, we are also proposing a "multifunctional" regulatory role for TNFR1 by demonstrating its specific response to proteins from the innate immunity cascade.…”

Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors

“…However, as shown here, this molecule can inhibit not only TNF but also LT␣ and LT␤, two potentially unfavorable activities. Indeed, these cytokines are essential for the control of immune homeostasis and infections (42,43), and an increased risk of infections, autoimmune disorders, and cancer are documented side effects of etanercept. Thus, molecular redesign of this medicine seems to be necessary to target TNF specifically and avoid undesirable effects.…”