IL-17 producing T cells in human chronic inflammatory disease

A major interest of the lab is IL-17 biology. The IL-17 family consist of IL-17A, B, C, D, E and F. IL-17A is a potent pro-inflammatory cytokine which promotes angiogenesis, osteoclastogenesis and inflammatory cytokine and chemokine production. IL-17A-producing T cells are therefore thought to play a pivotal role in the immunopathology of inflammatory arthritis. Using multiparameter flow cytometry, RNA sequencing, Luminex, cellular and functional assays, we have studied the presence, function and regulation of IL-17A producing CD4+ (Th17) and CD8+ (Tc17) T cells in the context of rheumatoid and psoriatic arthritis. Through these efforts, we have identified that activated monocytes play an important role in promoting human Th17 cell induction. We have also discovered that whilst Th17 cells are enriched in the synovial fluid in both RA and PsA, Tc17 cells are only enriched in the inflamed PsA joint. These Tc17 cells have a pro-inflammatory profile and a tissue-resident memory phenotype. Ongoing work is aimed at determining the pro-inflammatory function of Tc17 cells and how these cells are regulated. We are also interested in understanding the function of the other IL-17 family members in the context of arthritis.

Regulation of CD4+ T cell function by TNF blockade

Effector CD4+ T cells are important contributors to the chronic joint inflammation in rheumatoid arthritis (RA), through their production of pro-inflammatory cytokines. Importantly, effector CD4+ T cells can also produce the potent anti-inflammatory cytokine interleukin-10 (IL-10), thereby limiting excessive tissue damage. Detailed understanding of how IL-10 is regulated is therefore scientifically and clinically important. Our lab previously demonstrated that tumour necrosis factor (TNF)-blocking drugs, which are widely used in the treatment of RA, promote IL-10 expression in human CD4+ T cells. We now aim to determine the molecular mechanisms via which TNF blockade regulates the expression of IL-10 in human pro-inflammatory CD4+ T cells and to determine what the functional consequences are. Using molecular, genetic, epigenetic, bioinformatics, flow cytometric, cellular and CyTOF analysis we study how TNF blockade influences regulation of IL-10 in human pro-inflammatory CD4+ T cells at the DNA, RNA and protein level. We also study the function and stability of TNF-blockade-induced IL-10 expressing CD4+ T cells. Through this work, we hope to reveal new molecular mechanisms of TNF blockade and possible biomarkers of response to anti-TNF therapy.

Versus arthritis research project determining the molecular mechanisms

Regulation of human monocyte function

CD14+ monocytes are abundantly present in the inflamed arthritic joint and have an activated phenotype. Our lab is interested to determine how we can modulate the inflammatory function of monocytes. For this, we focus on two research lines: (1) Treg-mediated modulation of monocytes: The suppressive effects of CD4+CD25+ regulatory T cells (Tregs) on adaptive immunity are well established; however, the effects on cells from the innate immune system are less well defined. We previously showed that CD4+CD25+ Tregs exert direct suppressive effects on monocytes and macrophages resulting in impaired T cell-stimulatory capacity, a reduced ability to respond to LPS, and an alternatively activated phenotype. In contrast, CD4+CD25- effector T cells induce a strong inflammatory response and subsequent apoptosis in monocytes and macrophages. Both outcomes are likely important for the maintenance of immune homeostasis, however, when dysregulated, they may contribute to chronic inflammation. Using functional assays, RNAseq and bioinformatic analysis, we hope to identify the molecular pathways underlying the Treg-induced anti-inflammatory function of monocytes, (2) Role of microRNAs in monocyte phenotype and effector function: Through detailed molecular and functional characterisation of CD14+ monocytes/macrophages from the inflamed tissue versus the blood of patients with active arthritis, we previously identified certain microRNAs that are differentially expressed in CD14+ cells from the site of inflammation. Ongoing research aims to determine how these microRNAs affect monocyte phenotype and function.

Regulatory T cells in human health and disease

For many years, the Taams lab has studied the presence and function of CD4+CD25+ regulatory T cells (Tregs) in human health and disease. When studying Tregs in RA, we found that Tregs maintain their regulatory phenotype and suppressive function during inflammation or inflammatory disease. Thus, inflammation does not necessarily impair immune regulation. Our lab continues to investigate the molecular profile and function of Tregs in the context of human health and chronic inflammation.

Neuro-immune interactions in health and disease

Chronic inflammation affects both physical and mental health aspects. Our lab has a strong interest in understanding how the immune and nervous systems interact to drive not just inflammation but also pain, fatigue depression, or neurodegeneration. The recently awarded Wellcome Trust PhD Training Programme in Neuro-Immune Interactions in Health and disease, co-directed with Franziska Denk and Stephen McMahon, will help create a strong interdisciplinary research network at King’s to bring together research and clinical excellence in inflammation biology, neuroscience and mental health to answer critical questions in neuro-immune research.

Wellcome Trust PhD Programme in Neuro-immune interactions