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Structural and functional changes of the invariant NKT clonal repertoire in early rheumatoid arthritis.

Structural and functional changes of the invariant NKT clonal repertoire in early rheumatoid arthritis.
Structural and functional changes of the invariant NKT clonal repertoire in early rheumatoid arthritis.
Invariant NKT cells (iNKT) are potent immunoregulatory T cells that recognize CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions, including rheumatoid arthritis (RA), a clear understanding of the intrinsic mechanisms, including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease, is lacking. In this study, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analyzed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d Ag presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA, and their frequency was inversely correlated to disease activity score 28. Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, high-affinity iNKTs in early RA exhibited an altered functional Th profile with Th1- or Th2-like phenotype, in treatment-naive and treated patients, respectively, compared with Th0-like Th profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation, and our findings could be exploited for future therapeutic intervention.
0022-1767
5582-5591
Mansour, Salah
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Tocheva, Anna S.
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Sanderson, Joseph P.
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Goulston, Lyndsey M.
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Platten, Helen
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Serhal, Lina
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Parsons, Camille
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Edwards, Mark H.
b81ff294-1d16-4a1b-af14-9374c5989d4c
Woelk, Christopher H.
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Elkington, Paul T.
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Elliott, Tim
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Cooper, Cyrus
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Edwards, Christopher J.
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Gadola, Stephan D.
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Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Tocheva, Anna S.
f428e2af-7338-4cf3-bb12-9fe37e4fcbb0
Sanderson, Joseph P.
55f9cdfc-ab1e-4b84-8c02-83c4d51cfcfe
Goulston, Lyndsey M.
f0c12aca-b683-4093-98dc-f0ad99e022d9
Platten, Helen
6b0d6b95-464f-4276-b9fa-ea45ad8d8df1
Serhal, Lina
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Parsons, Camille
9730e5c3-0382-4ed7-8eaa-6932ab09ec15
Edwards, Mark H.
b81ff294-1d16-4a1b-af14-9374c5989d4c
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Elkington, Paul T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Edwards, Christopher J.
dcb27fec-75ea-4575-a844-3588bcf14106
Gadola, Stephan D.
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1

Mansour, Salah, Tocheva, Anna S., Sanderson, Joseph P., Goulston, Lyndsey M., Platten, Helen, Serhal, Lina, Parsons, Camille, Edwards, Mark H., Woelk, Christopher H., Elkington, Paul T., Elliott, Tim, Cooper, Cyrus, Edwards, Christopher J. and Gadola, Stephan D. (2015) Structural and functional changes of the invariant NKT clonal repertoire in early rheumatoid arthritis. Journal of Immunology, 195 (12), 5582-5591. (doi:10.4049/jimmunol.1501092). (PMID:1501092)

Record type: Article

Abstract

Invariant NKT cells (iNKT) are potent immunoregulatory T cells that recognize CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions, including rheumatoid arthritis (RA), a clear understanding of the intrinsic mechanisms, including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease, is lacking. In this study, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analyzed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d Ag presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA, and their frequency was inversely correlated to disease activity score 28. Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, high-affinity iNKTs in early RA exhibited an altered functional Th profile with Th1- or Th2-like phenotype, in treatment-naive and treated patients, respectively, compared with Th0-like Th profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation, and our findings could be exploited for future therapeutic intervention.

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Accepted/In Press date: 9 October 2015
e-pub ahead of print date: 9 November 2015
Published date: 9 November 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 384342
URI: https://eprints.soton.ac.uk/id/eprint/384342
ISSN: 0022-1767
PURE UUID: eca094ef-a46f-452b-b261-075bc14b9e23
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X
ORCID for Paul T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for Tim Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

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Date deposited: 21 Dec 2015 12:09
Last modified: 06 Jun 2018 13:00

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Contributors

Author: Salah Mansour ORCID iD
Author: Anna S. Tocheva
Author: Joseph P. Sanderson
Author: Lyndsey M. Goulston
Author: Helen Platten
Author: Lina Serhal
Author: Camille Parsons
Author: Mark H. Edwards
Author: Tim Elliott ORCID iD
Author: Cyrus Cooper ORCID iD
Author: Stephan D. Gadola

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