Increase in inflammatory T cell subsets in atrial fibrillation: the missing link underlying inflammation in AF

Abstract

Abstract Background The precise role of inflammation in the development and perpetuation of atrial fibrillation (AF) is yet to be fully uncovered. T lymphocytes have pivotal roles in orchestrating inflammation. Specialised subsets of lymphocytes either promote or prevent inflammation. We are investigating a unique subset of lymphocytes, the CD4+CD28null T cells that expand in patients with chronic inflammation. These cells secrete high levels of pro-inflammatory cytokines and have cytolytic function. CD4+CD28null T cells are normally maintained under control by regulatory T cells (Treg), a specialised subset of T lymphocytes with suppressive function that maintain immune homeostasis and prevent pathogenic immune responses. The role of CD4+CD28null and Treg cells has not been investigated in AF. Purpose We hypothesised that in AF the balance between pro-inflammatory and regulatory T lymphocytes is skewed in favour of inflammatory T cells, which may sustain inflammation in AF. Methods Circulating CD4+CD28null T lymphocytes and Tregs were quantified by flow cytometry in paroxysmal and persistent AF patients and healthy controls (n=30). Inflammatory cytokines were quantified in serum and the function of T lymphocyte subsets was investigated using ex vivo functional assays. Results CD4+CD28null T lymphocytes were significantly increased in the circulation of AF patients compared to controls. Of note, a higher proportion of patients with persistent AF showed an increase in inflammatory CD4+CD28null T lymphocytes compared to patients with paroxysmal AF. A marked reduction in Treg cells was present in AF patients compared to controls. Functional assays showed that IL-7 and IL-15 cytokines were responsible for CD4+CD28null T lymphocyte expansion in AF patients. Conclusions We show that patients with AF have marked changes in T lymphocytes subsets: pro-inflammatory CD4+CD28null T cells increase significantly, whilst anti-inflammatory Tregs are significantly reduced. We show for the first time that the cytokines IL-7 and IL-15 are the main drivers of CD4+CD28null T cell expansion in AF patients. These novel findings may reveal novel therapeutic strategies (e.g. cytokine blockade) to re-establish the balance between pro- and anti-inflammatory mechanisms at work in AF to improve patient outcomes. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation