Mansour, Salah, Tocheva, Anna, Sanderson , Joseph, Goulston, Lyndsey, Platten, Helen, Serhal, Lina, Parsons, Camille, Edwards, Mark, Woelk, Christopher, Elkington, Paul, Elliott, Tim, Cooper, Cyrus, Edwards, Christopher and Gadola, Stephan (2015) Invariant NKT cells in early Rheumatoid Arthritis. Structural and functional changes of the iNKT clonal repertoire in early Rheumatoid Arthritis.

Abstract

Invariant Natural Killer T cells (iNKT) are potent immunoregulatory T cells which recognise 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. Here, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analysed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d antigen 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 (DAS28). 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 T-helper profile with Th1 or Th2-like phenotype, in treatment-naive and treated patients respectively, compared to Th0-like T-helper 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.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27634