Taams Research Group
The overall mission of the Taams lab is to identify fundamental cellular and molecular mechanisms that initiate, perpetuate and regulate immune-mediated inflammation in human health and disease. Our long-term goal is to identify novel targets/pathways for therapeutic intervention of inflammation and to better inform treatment decisions. To achieve this, the lab works in a multi-disciplinary environment with strong clinical, academic and industrial collaborations.
Our lab has a specific interest in T cell, monocyte and cytokine biology, and how these cells and mediators influence the ensuing immune response. The lab combines in vitro models with ex vivo and in situ studies using human cells and tissue samples to investigate the presence, induction and regulation of pro-inflammatory and anti-inflammatory immune cells and their interaction with the tissue environment. We translate our questions and findings by studying rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as key examples of chronic inflammatory diseases and as model systems to investigate the immune system at the site of inflammation in humans. For this, we work in close collaboration with Prof Bruce Kirkham and his team at the Dept Rheumatology, Guy’s Hospital.
Our current research programmes include:
1) Presence, function and regulation of IL-17 producing T cells in human chronic inflammatory disease
2) Regulating the pro-inflammatory function of human T cells by TNF blockade
IL-17 (IL-17A) is a highly pro-inflammatory and osteoclastogenic cytokine and IL-17 producing T cells are therefore thought to play a pivotal role in the immunopathology of inflammatory arthritis. Our work in this area focuses on two themes:
Theme 1. Th17 cells in rheumatoid arthritis
We and others have shown that IL-17 producing CD4+ T cells (Th17 cells) are present at increased frequencies in the blood, synovial tissue and synovial fluid of patients with RA (Gullick et al. PLoSOne 2010; Gullick et al. Clin Exp Immunol 2013), and that the presence of these cells correlates with parameters of active disease (Gullick et al. PLoSOne 2010). In addition, we found that both in vitro activated (LPS-stimulated) and in vivo activated CD14+ cells from the inflamed RA joint are potent drivers of IL-17 production in CD4+ T cells (Evans et al. PNAS 2007; Evans et al. PNAS 2009). Understanding what drives a Th17 response (including IL-17A and IL-17F production) in humans, and how this can be regulated, remains a key objective of the lab.
Theme 2. Tc17 cells in psoriatic arthritis
Psoriatic Arthritis (PsA) is an inflammatory arthritis that is genetically, serologically and clinically distinct from RA. Our lab has shown that the inflamed joint of patients with PsA is enriched for IL-17 producing CD8+ T cells (Tc17) and that these cells correlate with clinical parameters of disease (Menon et al. Arthritis Rheumatol 2014). Current work aims to phenotypically, functionally and molecularly characterise human Tc17 cells, in order to define how these cells might contribute to the immunopathology of PsA (Taams et al. Nature Rev Rheumatol 2018).
3) Regulating the pro-inflammatory function of human monocytes and macrophages
Our lab has shown that TNF-α blockade, which is widely used in the treatment of immune-mediated inflammatory diseases, induces IL-10 expression in CD4+ and CD8+ T cells, including IL-17 producing T cells (Evans et al. Nat Commun 2014; Roberts et al. Frontiers Immunol 2017). This may contribute to the anti-inflammatory action of TNF inhibitors. Current work, funded by an Arthritis Research UK programme grant, is aimed at defining the molecular mechanisms underlying IL-10 expression in CD4+ T helper cells in vitro and in vivo and at determining the functional consequences of IL-10 expression in CD4+ T cells.
4) Presence and function of regulatory T cells during inflammation
CD14+ myeloid cells (monocytes and macrophages) are abundantly present in the inflamed arthritic joint and have an activated phenotype. As such, a better understanding of how we can modulate the inflammatory function of monocytes and macrophages could lead to novel therapeutic insights. We currently focus on two research lines:
Theme 1. Treg-mediated modulation of monocytes and macrophages
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/macrophages resulting in impaired T cell-stimulatory capacity, a reduced ability to respond to LPS, and an alternatively activated phenotype (Taams et al. Human Immunol 2005; Tiemessen et al. PNAS 2007). In contrast, CD4+CD25- effector T cells induce a strong inflammatory response and subsequent apoptosis in monocytes and macrophages (Jagger et al. J Autoimmunity 2012). Both outcomes are likely important for the maintenance of immune homeostasis, however when dysregulated, it may contribute to chronic inflammation. Our current work is aimed at identifying the molecular pathways underlying the Treg-induced anti-inflammatory function of monocytes/macrophages, using cellular assays and gene expression profiling.
Theme 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 identified certain microRNAs that are differentially expressed in CD14+ cells from the site of inflammation (Rajasekhar et al. J Autoimmunity 2017). We are currently determining how these microRNAs affect monocyte phenotype and function.
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 (van Amelsfort et al. Arthritis Rheum 2004; Walter et al. Arthritis Rheum 2013; Walter et al. Arthritis Rheumatol. 2016). 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.