Ankylosing spondylitis (AS) is a common immune-mediated arthritis that primarily affects the spine and pelvis. Common co-morbidities include psoriasis and Crohn;s-like gut disease. The drivers of inflammation in AS are not well described but recent genomic studies have identified several candidate immune pathways that are likely to play significant roles in AS pathogenesis. TBX21 encodes the transcription factor T-bet and is genome-wide significant associated with AS. T-bet is implicated in innate and adaptive immunity. However, the role of T-bet in AS pathogenesis is unclear.

AS patients have higher T-bet expression than healthy individuals, driven predominantly by NK and CD8+ T cells, with expression levels in CD8+ T cells completely distinguishing AS cases from healthy controls. In curdlan-treated SKG mice, T-bet expression increased early after disease initiation and persisted throughout the disease course. There was marked reduction in gut and peripheral joint inflammation, and fewer IFN-γ- and IL-17-producing CD8+ T cells, in Tbx21-/- compared with wild-type SKG mice. Tbx21 influenced the intestinal microbial composition with decreased abundance of inflammatory species such as Bacteroidaceae, Prevotellaceae, Rikenellaceae, Lachnospiraceae observed in Tbx21-/- compared with Tbx21+/+ SKG mice. T-bet+ NK cells and CD8 T cells secreted IL-17 and IFN-gamma following in vitro challenge with a range of TLR agonists. In the periphery of AS cases T-bet+ NK cells and CD8 T cells displayed phenotypic markers of recent antigen exposure but the frequnecy of circulating memory T cells was profoundly reduced compared with healthy controls.

AS-associated variants in TBX21 influence T-bet expression and numbers of IL-17 and IFN-gamma secreting NK and CD8+ T cells. T-bet is a major component of inflammatory pathways of spondyloarthropathy in humans and mice and may contribute to inflammation by influencing the gut microbiome and/or through influences on immune cell function in response to microbial challenge.