T cell regulation and adaptation in chronic inflammation: location matters

Abstract

T cells have an important role in autoimmune diseases as is underscored by genomic research and the abundance of T cells at sites of inflammation. However, in-depth knowledge about the regulation and function of different T cell subsets in local human inflammation is scarce. The recent discovery of tissue resident memory T (Trm) cells and the enormous diversity of regulatory T cell (Treg) subsets identified in different tissues have added a new layer of complexity. Juvenile Idiopathic arthritis (JIA) is an autoimmune disease characterized by chronic inflammation of the joints. As the disease can have a severe impact on the growing skeleton, current treatment strategies are aimed at preventing joint damage by general interference with inflammatory mediators. Treatment also involves intra-articular injections of corticosteroids following aspiration of the inflammatory exudate in the affected joints that allows research of human immune cells that actually take part in the inflammatory process. In this thesis we sought to dissect local immune regulation and T cell programming and adaptation in inflamed joints of Juvenile Idiopathic arthritis (JIA) patients. Analysis of the suppressive function of local SF derived Treg revealed an disruptive effect of the inflammatory environment on T cell regulation. Treg derived from peripheral blood as well as inflamed joints are fully functional. However, effector cells present in SF are unresponsive to Treg suppression due to heightened activation of protein kinase B (PKB)/c-akt that in part is induced by inflammatory mediators, such as TNFα and IL-6. Moreover, we identified an overrepresentation of CD8+PD1+ T cells in SF. From viral infections it is known that CD8+ T cells that express PD-1 are functionally exhausted. However, using gene expression profiling, T cell receptor profiling and functional studies we identified these cells as metabolically active effectors that are clonally expanding and enriched for a Trm profile. Also in target tissues of other human chronic inflammatory diseases increased amounts of this subset were found. These data indicate that CD8+PD1+ T cells represent potential new therapeutic targets. To further study the environment-adapted programming of human Treg, we combined transcriptional and epigenetic profiling of SF Treg. Our data revealed upregulation of core Treg markers as well as effector Treg markers, guided by changes in the (super-)enhancer landscape compared to Treg from blood. The observed profile showed striking overlap with tumor-infiltrating Treg. Thus inflammation seems to induce a specific Treg profile that is fine-tuned by environment-specific adaptations. Additionally, we identified an extensive overlap in T cell immune architecture and specific dominant T(reg) cell clones in anatomically distinct inflammatory sites within a patient. Also, these dominant T cell clones persist over the relapsing-remitting course of disease and can be traced in circulation. Taken together, the studies described in this thesis provide novel insight into T cell regulation and programming in local autoimmune-inflammation. Targeting resistance of effector T cells as wells as aggressive CD8+PD1+ T cells could be of therapeutic interest, whereas circulating clonal T cells similar to those found in the joint can be of clinical interest for monitoring and targeting.