The characterisation of human  T cells in health and disease; Do V9V2 T cells play a role in the pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)?

Abstract

Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a chronic necrosis of the jawbone that occurs in 1-5% of patients receiving bisphosphonate medication for conditions such as osteoporosis and certain cancers. Although the pathogenesis of BRONJ is still uncertain, several recent theories have emerged; these include vascular disruption of the jaw tissue; inappropriate osteoclast activation; and direct cytotoxicity of jaw epithelium. However, despite bisphosphonates having well-documented stimulatory effects on immune cells, and BRONJ being associated with oral microbial infections, an immune-mediated pathology for BRONJ has largely been ignored. Bisphosphonates activate human  T cells, specifically those that use T cell receptor (TCR) -chain variable-region-9, and TCR -chain variable-region-2 (V9V2 T cells). These unconventional T cells typically account for 1-5% of circulating lymphocytes, make protective responses to microbial challenge, and are promising candidates for cancer immunotherapy. In the context of BRONJ, we have hypothesised that bisphosphonate-mediated activation of jaw-associated V9V2 T cells, in the presence of oral microbiota, may drive the disruption of bone turnover that is central to the disease process. On initiation of these studies, it quickly became apparent that traditional characterisation of V9V2 T cells using CD27/CD45RA was demonstrably sub-optimal, while phenotypic analysis of 63 healthy volunteers revealed an unexpected and surprising degree of V9V2 T cell heterogeneity; both of which are likely to confuse assessment of disease scenarios. Thus, this thesis describes the novel phenotypic and functional characterisation of V9V2 T cells using alternative surface markers and methods of analysis. This reveals that different sets of individuals have different V9V2 T cell “profiles” that predict very different functional capabilities and responses to immunotherapeutic interventions. Using this improved definition of V9V2 T cells, this thesis then describes preliminary investigations of V9V2 T cell development in the human neonatal thymus, and assesses the involvement of V9V2 T cells in a small cohort of eight BRONJ patients.