T cell-mediated immune regulation in spondyloarthritis

Thesis

CD4+ T cells are essential components of the immune system. Dysregulated or excessive T cell responses can cause, in susceptible individuals, a group of immune-mediated conditions termed Spondyloarthritis (SpA), characterized by chronic inflammation and structural damage of various musculoskeletal structures. While well-documented genetic and immunological alterations in SpA explain the overactivation of effector T cells, the intrinsic regulatory functions exerted by a specialized T cell subset (Tregs) have been studied only marginally. Exploring the natural suppressive functions of Tregs could reveal novel regulatory pathways that can be leveraged for patient benefit.

In its first part, this thesis focuses on the phenotypic and transcriptional diversity of regulatory T cells in the peripheral blood and synovial fluid in Spondyloarthritis. Through the use of high-resolution techniques and unbiased analytical methods, I identify and characterize specialized regulatory subsets in the blood and joints of patients with SpA. One of these subsets, which presents features shared with Th17 cells and similarities with intestinal Tregs, preferentially expresses the regulatory markers IL-10 and LAG-3. LAG-3, in particular, is an emerging inhibitory receptor expressed on T cells. I show that LAG-3 is able to control blood-derived monocyte activation in vitro, reducing production of the inflammatory cytokines IL-12/23 and TNF, and downregulating costimulatory molecules necessary for T effector activation. This mechanism is predicted to restrain inflammatory responses, making LAG-3-based therapeutic interventions promising novel strategies for immune driven diseases such as SpA.

A further emerging therapeutic strategy for SpA and other inflammatory arthritides consists in targeting inflammatory signaling pathways. The intracellular kinase MK2 is involved in the post-transcriptional regulation of cytokine expression. In the last part of the thesis I show that a novel small molecule MK2 inhibitor is effective in reducing T cell mediated inflammatory responses, including Th17, making it a promising novel therapeutic agent for SpA.

Authors: Simone, D

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: adaptive immunity; T cell; spondyloarthritis; immunology