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Cleavage of TL1A differentially regulates its effects on innate and adaptive immune cells

Cleavage of TL1A differentially regulates its effects on innate and adaptive immune cells
Cleavage of TL1A differentially regulates its effects on innate and adaptive immune cells
Tumor necrosis factor (TNF) superfamily cytokines play major roles in the regulation of both adaptive and innate immunity. The TNF superfamily cytokine TL1A (TNFSF15) through its cognate receptor DR3 (TNFRSF25) promotes T cell immunity to pathogens and directly costimulates group 2 and 3 innate lymphoid cells. Polymorphisms in the TNFSF15 gene are associated with risk for various human diseases including inflammatory bowel disease. Like other cytokines in the TNF superfamily, TL1A is synthesized as a type II transmembrane protein and cleaved from the plasma membrane by metalloproteinases. Membrane cleavage has been shown to alter or abrogate certain activities of other TNF-family cytokines, but for TL1A, the functional capabilities of membrane bound and soluble forms of this cytokine are not known. Constitutive expression of TL1A in transgenic mice results in expansion of activated T cells and promotes intestinal hyperplasia and inflammation through stimulation of group 2 innate lymphoid cells. Through the generation of membrane restricted TL1A transgenic mice, we demonstrate that membrane TL1A promotes expression of inflammatory cytokines in the lung, dependent on DR3 expression on T cells. Soluble TL1A alone was unable to produce this phenotype but was still able to induce intestinal type 2 inflammation independently of T cells. These data suggest differential roles of membrane and soluble TL1A on adaptive and innate immune cells, and have implications for the consequences of blocking these two forms of TL1A.
0022-1767
1360-1369
Ferdinand, John R.
dde0ef72-6949-4ad8-837a-474978b65623
Richard, Arianne C.
6e7559e3-dac3-4cca-bfba-d0ae3e0b3ddf
Meylan, Françoise
7e685769-11bc-4063-b327-e4f75f190b0f
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Siegel, Richard M.
846baa3b-a852-44f6-8a74-ed560101d0f4
Ferdinand, John R.
dde0ef72-6949-4ad8-837a-474978b65623
Richard, Arianne C.
6e7559e3-dac3-4cca-bfba-d0ae3e0b3ddf
Meylan, Françoise
7e685769-11bc-4063-b327-e4f75f190b0f
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Siegel, Richard M.
846baa3b-a852-44f6-8a74-ed560101d0f4

Ferdinand, John R., Richard, Arianne C., Meylan, Françoise, Al-Shamkhani, Aymen and Siegel, Richard M. (2018) Cleavage of TL1A differentially regulates its effects on innate and adaptive immune cells. The Journal of Immunology, 200 (4), 1360-1369. (doi:10.4049/jimmunol.1700891).

Record type: Article

Abstract

Tumor necrosis factor (TNF) superfamily cytokines play major roles in the regulation of both adaptive and innate immunity. The TNF superfamily cytokine TL1A (TNFSF15) through its cognate receptor DR3 (TNFRSF25) promotes T cell immunity to pathogens and directly costimulates group 2 and 3 innate lymphoid cells. Polymorphisms in the TNFSF15 gene are associated with risk for various human diseases including inflammatory bowel disease. Like other cytokines in the TNF superfamily, TL1A is synthesized as a type II transmembrane protein and cleaved from the plasma membrane by metalloproteinases. Membrane cleavage has been shown to alter or abrogate certain activities of other TNF-family cytokines, but for TL1A, the functional capabilities of membrane bound and soluble forms of this cytokine are not known. Constitutive expression of TL1A in transgenic mice results in expansion of activated T cells and promotes intestinal hyperplasia and inflammation through stimulation of group 2 innate lymphoid cells. Through the generation of membrane restricted TL1A transgenic mice, we demonstrate that membrane TL1A promotes expression of inflammatory cytokines in the lung, dependent on DR3 expression on T cells. Soluble TL1A alone was unable to produce this phenotype but was still able to induce intestinal type 2 inflammation independently of T cells. These data suggest differential roles of membrane and soluble TL1A on adaptive and innate immune cells, and have implications for the consequences of blocking these two forms of TL1A.

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Accepted/In Press date: 11 December 2017
e-pub ahead of print date: 5 February 2018
Published date: 15 February 2018

Identifiers

Local EPrints ID: 417116
URI: https://eprints.soton.ac.uk/id/eprint/417116
ISSN: 0022-1767
PURE UUID: b3d76ec3-fcb1-4adb-b83d-b3e06c105448
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 19 Jan 2018 17:30
Last modified: 14 Mar 2019 01:49

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Contributors

Author: John R. Ferdinand
Author: Arianne C. Richard
Author: Françoise Meylan
Author: Richard M. Siegel

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