T cell phenotype and function in Spondyloarthritis

Thesis

Th17 cells are implicated in a variety of inflammatory disorders including Spondyloarthritis (SpA). Ankylosing spondylitis (AS), the most common SpA, is genetically associated with HLA-B27 and IL-23R polymorphisms, although the link remains unexplained. 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.

I have shown an expansion of KIR3DL2+ CD4+ T cells in peripheral blood of AS patients and HLA-B27+ healthy controls. Although KIR3DL2+ CD4+ T cells comprise a minority of CD4+ T cells in peripheral blood, KIR3DL2+ CD4+ T cells account for the majority of peripheral blood CD4+ T cell IL-23R expression. KIR3DL2+ CD4+ T cells from synovial fluid are also enriched for IL-23R expression compared to matched peripheral blood samples. Moreover, treatment exposure to rIL-1/23 significantly increases IL-17 production by KIR3DL2+ CD4+ T cells in AS patients but not RA patients and healthy controls.

KIR3DL2+ CD4+ T cells from AS patients produce more IL-17 than KIR3DL2+ CD4+ T cells from HLA-B27- healthy controls. KIR3DL2+ CD4+ T cells from AS patients and healthy controls are also enriched for dual production of IL-17 and IFNγ, consistent with the theory that AS is a Th17 or a Th17/1 driven disease.

I have shown that naïve CD4+ T cells express KIR3DL2 de novo after activation. Interaction with B272-expressing cells acts to maintain and/or further increase KIR3DL2 expression. Interaction with B272-expressing cells also increases expression of Bcl-2. I propose that interaction of KIR3DL2+ CD4+ T cells with B272 preferentially promotes the survival of these pro-inflammatory cytokine-producing KIR3DL2+ CD4+ T cells in SpA. HD6, a B272-specific monoclonal antibody, decreases IL-17 production by PBMCs from AS patients, making it an attractive candidate therapeutic reagent in the treatment of AS and other HLA-B27-associated SpA.

Authors: Ridley, AL

• Publication date: 2013
• DOI: 10.5287/ora-mj5o5r8ao
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Th17; immunomodulatory receptors; HLA-B27; Spondyloarthritis
• Subjects: Immunology