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The clonal iNKT cell repertoire in people with type 1 diabetes is characterized by a loss of clones expressing high-affinity T cell receptors

The clonal iNKT cell repertoire in people with type 1 diabetes is characterized by a loss of clones expressing high-affinity T cell receptors
The clonal iNKT cell repertoire in people with type 1 diabetes is characterized by a loss of clones expressing high-affinity T cell receptors
Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production. Our results demonstrate a selective loss of clones expressing high-affinity iNKT-TCRs from the iNKT repertoire of people with type 1 diabetes. Furthermore, this bias in the clonal iNKT repertoire in type 1 diabetes was associated with increased GM-CSF, IL-4, and IL-13 cytokine secretion among Ag-stimulated low-affinity iNKT clones. Thus, qualitative changes of the clonal iNKT repertoire with the potential to affect the regulatory function of this highly conserved T cell population are already established at the early stages in type 1 diabetes. These findings may inform future rationales for the development of iNKT-based therapies aiming to restore immune tolerance in type 1 diabetes.
0022-1767
1452-1459
Tocheva, Anna S.
f428e2af-7338-4cf3-bb12-9fe37e4fcbb0
Mansour, Salah
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Holt, Tristan G.H.
759979ac-26e1-4664-8669-1e43edf9f19a
Jones, Samuel
f408b12a-831c-4e92-814b-2ac4d3a5b023
Chancellor, Andrew
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Sanderson, Joseph P.
55f9cdfc-ab1e-4b84-8c02-83c4d51cfcfe
Eren, Efrem
ac449fc8-4ae2-4efd-ad91-9dcea3f355e2
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Holt, Richard
d54202e1-fcf6-4a17-a320-9f32d7024393
Gadola, Stephan
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1
Tocheva, Anna S.
f428e2af-7338-4cf3-bb12-9fe37e4fcbb0
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Holt, Tristan G.H.
759979ac-26e1-4664-8669-1e43edf9f19a
Jones, Samuel
f408b12a-831c-4e92-814b-2ac4d3a5b023
Chancellor, Andrew
1ea3cb23-ec95-45ee-9ace-b711170c226b
Sanderson, Joseph P.
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Eren, Efrem
ac449fc8-4ae2-4efd-ad91-9dcea3f355e2
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Holt, Richard
d54202e1-fcf6-4a17-a320-9f32d7024393
Gadola, Stephan
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1

Tocheva, Anna S., Mansour, Salah, Holt, Tristan G.H., Jones, Samuel, Chancellor, Andrew, Sanderson, Joseph P., Eren, Efrem, Elliott, Timothy, Holt, Richard and Gadola, Stephan (2017) The clonal iNKT cell repertoire in people with type 1 diabetes is characterized by a loss of clones expressing high-affinity T cell receptors. The Journal of Immunology, 198 (4), 1452-1459. (doi:10.4049/jimmunol.1600255).

Record type: Article

Abstract

Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production. Our results demonstrate a selective loss of clones expressing high-affinity iNKT-TCRs from the iNKT repertoire of people with type 1 diabetes. Furthermore, this bias in the clonal iNKT repertoire in type 1 diabetes was associated with increased GM-CSF, IL-4, and IL-13 cytokine secretion among Ag-stimulated low-affinity iNKT clones. Thus, qualitative changes of the clonal iNKT repertoire with the potential to affect the regulatory function of this highly conserved T cell population are already established at the early stages in type 1 diabetes. These findings may inform future rationales for the development of iNKT-based therapies aiming to restore immune tolerance in type 1 diabetes.

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Accepted/In Press date: 5 December 2016
e-pub ahead of print date: 15 February 2017
Published date: 15 February 2017
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 403840
URI: https://eprints.soton.ac.uk/id/eprint/403840
ISSN: 0022-1767
PURE UUID: 932eb8f0-d8ae-4a21-a6d0-3eb66eecde28
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Richard Holt: ORCID iD orcid.org/0000-0001-8911-6744

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Date deposited: 15 Dec 2016 09:09
Last modified: 26 Nov 2019 01:52

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Contributors

Author: Anna S. Tocheva
Author: Salah Mansour ORCID iD
Author: Tristan G.H. Holt
Author: Samuel Jones
Author: Andrew Chancellor
Author: Joseph P. Sanderson
Author: Efrem Eren
Author: Timothy Elliott ORCID iD
Author: Richard Holt ORCID iD
Author: Stephan Gadola

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