The T Cell Costimulator TL1A Is Induced by FcγR Signaling in Human Monocytes and Dendritic Cells

Abstract

The recently described TL1A/DR3 ligand/receptor pair mediates strong costimulation of Th1 cells. Activation of T and NK cells induces DR3 expression, permitting soluble recombinant TL1A to increase IFN-γ production and proliferation of these cells. Gut T cells and macrophages express TL1A, especially in Crohn’s disease (CD), and there is a strong association between CD and tl1a single nucleotide polymorphisms. Murine studies implicate TL1A in gut inflammation. To determine whether professional T cell-activating cells can express TL1A, fresh blood monocytes and monocyte-derived dendritic cells were stimulated with various activating ligands, including TLR agonists, IFN-γ, and immune complexes. FcγR stimulation strongly induced TL1A mRNA in both cell types, which correlated with the detection of TL1A on the cell surface and in cell culture medium. TLR agonists capable of inducing IL-6 and TNF-α in monocytes and dendritic cells did not induce surface nor soluble TL1A. Furthermore, we demonstrate that TL1A production in monocytes leads to enhancement of T cell responses. The induction of TL1A on APCs via specific pathway stimulation suggests a role for TL1A in Th1 responses to pathogens, and in CD.

Cloning, Expression, and Functional Characterization of TL1A-Ig

“…TL1A upregulation is reported on endothelial cells after stimulation with inflammatory cytokines such as IL-1 and TNF. Macrophages and dendritic cells display increased TL1A after stimulation with TLR ligands and Fc receptor cross-linking (9,11). Moreover, TL1A ligation of TNFRSF25 on CD4 + and CD8 + T cells enhances the production of a wide variety of cytokines, including IL-2, IL-4, and IFN-g, subsequent to TCR signaling via NF-kB-associated pathways (9,12).…”

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

“…A second DR3 antibody showed similar results. TNFSF15 is expressed on human MDM (18). Surface TNFSF15 increased following NOD2 stimulation, peaking 12-24 h after treatment with 100 μg/mL MDP (dosed as per prior studies; refs.…”

Modulation of TNFSF expression in lymphoid tissue inducer cells by dendritic cells activated with Toll-like receptor ligands

“…Although DCs did not upregulate TNFRSF expression, it is possible that cytokines secreted by DCs influenced LTi cell surface expression. It is known that OX40L and TRANCE expression on LTi cells is upregulated by TL1A, a TNF-like ligand (25), whereas DCs activated with TLR ligands do not induce TL1A; instead DCs stimulated through FcγR induce TL1A (26). In addition, IL-7 upregulates CD30L on LTi cells, whereas DCs do not express IL-7 and require a 5-day culture (27).…”