The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

Chiara Cavallini,Luciano Pacelli,Elisa Zoratti,Ornella Lovato,Cristina Tecchio,Marco A Cassatella,Anna Bertolaso,Giovanni Pizzolo,Elisabetta Zanolin,Alberto Zamò,Maria T Scupoli,Mauro Krampera,Raffaella Bonecchi

doi:10.1371/journal.pone.0060136

Abstract

Death receptor (DR3) 3 is a member of the TNFR superfamily. Its ligand is TNF-like ligand 1A (TL1A), a member of the TNF superfamily. TL1A/DR3 interactions have been reported to modulate the functions of T cells, NK, and NKT cells and play a crucial role in driving inflammatory processes in several T-cell-dependent autoimmune diseases. However, TL1A expression and effects on B cells remain largely unknown. In this study, we described for the first time that B cells from human blood express significant amounts of DR3 in response to B cell receptor polyclonal stimulation. The relevance of these results has been confirmed by immunofluorescence analysis in tonsil and spleen tissue specimens, which showed the in situ expression of DR3 in antigen-stimulated B cells in vivo. Remarkably, we demonstrated that TL1A reduces B-cell proliferation induced by anti-IgM-antibodies and IL-2 but did not affect B-cell survival, suggesting that TL1A inhibits the signal(s) important for B-cell proliferation. These results revealed a novel function of TL1A in modulating B-cell proliferation in vitro and suggest that TL1A may contribute to homeostasis of effector B-cell functions in immune response and host defense, thus supporting the role of the TL1A/DR3 functional axis in modulating the adaptive immune response.

Highlights

Death receptor (DR) 3 (TNFRSF25/Apo3/LARD/TR3/ TRAMP/WSL-1) is a member of the TNFR superfamily and, within that family, of the DR subfamily, whose members contain a death domain (DD) as part of their intracellular domain [1,2,3,4,5]
We describe for the first time that B cells from human blood express significant amounts of DR3 in response to the polyclonal stimulation of B cell receptor (BCR)
The relevance of these results has been confirmed by immunofluorescence analysis of tonsil and spleen tissue specimens, which show that antigen-stimulated B cells in tonsil germinal centers (GC) express high levels of DR3 whereas a few DR3-positive B cells are detectable in the white pulp of spleens showing rare GC

Summary

Introduction

Death receptor (DR) 3 (TNFRSF25/Apo3/LARD/TR3/ TRAMP/WSL-1) is a member of the TNFR superfamily and, within that family, of the DR subfamily, whose members contain a death domain (DD) as part of their intracellular domain [1,2,3,4,5]. Among the DR subfamily members, DR3 shows the highest homology to TNFR1 [3,4]. The ligand for DR3 is TNF-like ligand 1A (TL1A), a member of the TNF superfamily [7,8,9,10]. TL1A is expressed in a variety of cell types, including activated endothelial cells, monocytes, macrophages, dendritic cells, and T cells [7,11,12,13,14,15]. Like other TNF members, TL1A contains a predicted transmembrane domain and a bioactive, proteolytically cleaved truncated form that can be released as a soluble factor [7,8]. TL1A expression is highly regulated and induced by inflammatory stimuli [7,11,15,16]

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Results

Conclusion