ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1655

HLA-B27 and KIR3DL2 Interactions Promote The Differentiation and Survival Of Proinflammatory T Cells In Spondyloarthritis

A. Ridley1, I. Wong-Baeza2, H. Hatano2, J. Shaw2, H. Al-Mossawi2, P. Bowness2 and S. Kollnberger2, 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, United Kingdom, 2Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: T-cell Biology in Autoimmune Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: T helper 17 (Th17) cells are a subset of pro-inflammatory CD4+ T cells implicated in a number of inflammatory arthritides including the Spondyloarthritides (SpAs).  Ankylosing Spondylitis (AS), the commonest spondyloarthropathy, is genetically associated with HLA-B27 (B27) and IL-23 receptor polymorphisms, however the link remains unexplained.  We have previously shown KIR3DL2+ CD4+ T cells are expanded in the peripheral blood of individuals with AS. In addition to classically folded heterotrimers, HLA-B27 can form β2m-free homodimers (B272). B272, as well as free heavy chains, are able to interact with KIR3DL2. The aim of this study was to investigate whether KIR3DL2 expression was induced by activation of CD4+ T cells and to investigate the consequence of co-culturing HLA-B272-expressing cells with KIR3DL2+ CD4+ T cells.

Methods: Production of cytokines by PMA/ionomycin stimulated-peripheral blood mononuclear cells (PBMCs) was investigated by intracellular cytokine staining (ICS). KIR3DL2 expression by PMA/ionomycin stimulated-naïve CD4+ T cells was investigated by flow cytometry (FACS).  Expression of Bcl-2, RORC and T-bet by naïve CD4+ T cells was investigated using qPCR after co-culture with SEB stimulated-HLA-B272-expressing cells, or control HLA-expressing cells.

Results: KIR3DL2+ CD4+ T cells from AS patients are enriched for production of IL-17 (p<0.0001, n=16) and IL-17/IFNγ (p=0.002, n=8), as compared to KIR3DL2- CD4+ T cells. KIR3DL2+ CD4+ T cells from AS patients produce more IL-17 than KIR3DL2+ CD4+ T cells from HLA-B27- healthy controls (p=0.013). Naïve CD4+ T cells express KIR3DL2 de novo by FACS after activation (p=0.02, n=3). Co-culture of naïve CD4+ T cells with HLA-B272-expressing cells further increased KIR3DL2 expression and increased expression of the anti-apoptotic molecule Bcl-2.  Time-dependant alterations in RORC and T-bet expression were observed.

Conclusion: Expression of KIR3DL2 on naïve CD4+ T cells can be induced by activation. Co-culture of naïve CD4+ T cells with HLA-B272-expressing cells preferentially promotes the survival of KIR3DL2+ CD4+ T cells and promotes a Th17 (and Th1) transcriptional profile.  SpA KIR3DL2+ CD4+ T cells are enriched for production of IL-17 and for dual production of IL-17 and IFNγ, consistent with the theory that AS is a Th17 or a Th17/1 driven disease.

Disclosure:

A. Ridley,
None;

I. Wong-Baeza,
None;

H. Hatano,
None;

J. Shaw,
None;

H. Al-Mossawi,
None;

P. Bowness,
None;

S. Kollnberger,
None.

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