NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration

Kasper Vadstrup; Elisabeth Douglas Galsgaard; Helle Jensen; Lewis L. Lanier; James C. Ryan; Shih Yu Chen; Garry P. Nolan; Marianne Kajbæk Vester-Andersen; Julie Steen Pedersen; Jens Gerwien; Teis Jensen; Flemming Bendtsen

doi:10.1016/j.yexmp.2017.06.010

NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8⁺ T cell migration

Kasper Vadstrup^*, Elisabeth Douglas Galsgaard, Helle Jensen, Lewis L. Lanier, James C. Ryan, Shih Yu Chen, Garry P. Nolan, Marianne Kajbæk Vester-Andersen, Julie Steen Pedersen, Jens Gerwien, Teis Jensen, Flemming Bendtsen

^*Corresponding author for this work

Department of Clinical Medicine

8 Citations (Scopus)

Abstract

Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1–6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4–6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8⁺ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56⁺ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8⁺ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D⁺ lymphocytes into the inflamed CD intestine.

Original language	English
Journal	Experimental and Molecular Pathology
Volume	103
Issue number	1
Pages (from-to)	56-70
Number of pages	15
ISSN	0014-4800
DOIs	https://doi.org/10.1016/j.yexmp.2017.06.010
Publication status	Published - Aug 2017

Keywords

IBD
MICA
MICB
ULBP

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.yexmp.2017.06.010

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Cite this

Vadstrup, K., Galsgaard, E. D., Jensen, H., Lanier, L. L., Ryan, J. C., Chen, S. Y., Nolan, G. P., Vester-Andersen, M. K., Pedersen, J. S., Gerwien, J., Jensen, T., & Bendtsen, F. (2017). NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8⁺ T cell migration. Experimental and Molecular Pathology, 103(1), 56-70. https://doi.org/10.1016/j.yexmp.2017.06.010

Vadstrup, K, Galsgaard, ED, Jensen, H, Lanier, LL, Ryan, JC, Chen, SY, Nolan, GP, Vester-Andersen, MK, Pedersen, JS, Gerwien, J, Jensen, T & Bendtsen, F 2017, 'NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8⁺ T cell migration', Experimental and Molecular Pathology, vol. 103, no. 1, pp. 56-70. https://doi.org/10.1016/j.yexmp.2017.06.010

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title = "NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration",

abstract = "Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1–6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4–6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.",

keywords = "IBD, MICA, MICB, ULBP",

author = "Kasper Vadstrup and Galsgaard, {Elisabeth Douglas} and Helle Jensen and Lanier, {Lewis L.} and Ryan, {James C.} and Chen, {Shih Yu} and Nolan, {Garry P.} and Vester-Andersen, {Marianne Kajb{\ae}k} and Pedersen, {Julie Steen} and Jens Gerwien and Teis Jensen and Flemming Bendtsen",

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T1 - NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration

AU - Vadstrup, Kasper

AU - Galsgaard, Elisabeth Douglas

AU - Jensen, Helle

AU - Lanier, Lewis L.

AU - Ryan, James C.

AU - Chen, Shih Yu

AU - Nolan, Garry P.

AU - Vester-Andersen, Marianne Kajbæk

AU - Pedersen, Julie Steen

AU - Gerwien, Jens

AU - Jensen, Teis

AU - Bendtsen, Flemming

PY - 2017/8

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N2 - Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1–6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4–6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.

AB - Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1–6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4–6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.

KW - IBD

KW - MICA

KW - MICB

KW - ULBP

U2 - 10.1016/j.yexmp.2017.06.010

DO - 10.1016/j.yexmp.2017.06.010

M3 - Journal article

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SN - 0014-4800

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