Final Report Summary - STROMA (Stromal Cell- Immune Cell Interactions in Health and Disease)
The importance of stromal cells and the molecular mechanisms underpinning stromal cell function in the regulation of immune responses have only recently been appreciated and are an exciting new area in immunology. The purpose of STROMA was to ensure that Europe retains global leadership in this emerging field and to translate basic research on stromal cell-immune cell interactions to novel products and technologies for European industry. STROMA promoted the training of three Experienced Researchers (ERs) and thirteen Early Stage Researchers (ESR), combining research and training in state-of-the-art multidisciplinary technologies. Research conducted by STROMA represented the state of the art of the field, was wide ranging in nature and will have long-lasting impact.
In the thematic area of generating new tools for stromal cell research of benefit to the broader community, we generated new mouse lines to allow conditional deletion or lineage tracing of distinct stromal cell populations. We generated new monoclonal antibodies against stromal cell subsets, identifying antigens not previously characterised by others, and have produced multiple stroma-related transcriptomic data sets now in the public domain. We developed novel technologies for implanting stromal cells in human artificial lymph nodes and for seeding stromal cells onto solid substrates, designed to determine the impact of topography on stromal cell function, and developed machine learning algorithms and high-throughput image analysis to assess the effect of varying surface geometry. We have extended imaging modalities to study stromal in high resolution and in multiple dimensions, and developed approaches to study their mechanical properties.
In the thematic area of stromal cells and lymphoid tissue development and organisation, we discovered that adhesion molecule expression was heavily influenced by surface topography. We identified a novel link between the structural and functional adaptability of stromal cells with mechanical stress. We discovered that stromal cell re-organisation during LN hypertrophy induced by adjuvant-containing vaccines was regulated by a complex cytokine cascade. We have made important new discoveries on the lineage relationships between stromal cell subsets, including showing that splenic white pulp stromal cells arise from a common α-SMA+ progenitor. Our research has led to a reassessment of the role of mesenchymal lymphoid tissue organizer cells in SLO development. We identified new links between stromal cells and innate lymphoid cells. We identified expression of the neuroregulatory receptor RET in ILC3s, and identified lamina propria stromal cells as a potent source of RET ligands. We conducted gene profiling on human fetal LN stromal cells and innate lymphoid cells from LN and tonsils, identifying the breadth of pattern recognition receptor expression on these cells.
In the thematic area of infection, cancer and inflammation, we developed new tools to identify human stromal cell subsets, using these for the study of follicular lymphoma (FL) niches. We developed a new in vivo xenograft model and discovered that CXCL12 overexpression regulated by IL-4 could contributes to FL recruitment and should be considered as a new therapeutic target. Conversely, loss of CXCL12 was discovered to be one of the underlying mechanisms controlling the partial bone marrow failure observed in the parasitic disease visceral leishmaniasis. The collateral damage resulting from local IFNγ production also damages the hematopoietic stem cell pool. Our data suggest new therapeutic approaches to restoring bone marrow function in this globally important infectious disease. Using pre-clinical cancer models, we have begun to identify optimal modalities for the use of combination therapies targeting both T cell activation (e.g. PD-L1) and the tumour-associated vasculature. Finally, we discovered that stromal reticular cells activate lymphatic endothelial cells via RANKL, opening new opportunities for RANKL as a target in the treatment of chronic inflammatory and autoimmune diseases.
In summary, STROMA has generated new understanding of this important class of cells, helping to elevate them from their position as mere scaffolds underpinning immune architecture into cells with well-recognised and important immunoregulatory functions. The tools and methodologies developed in STROMA are being widely distributed across the scientific community and will fuel further academic, commercial and translational opportunities over the coming years.
In the thematic area of generating new tools for stromal cell research of benefit to the broader community, we generated new mouse lines to allow conditional deletion or lineage tracing of distinct stromal cell populations. We generated new monoclonal antibodies against stromal cell subsets, identifying antigens not previously characterised by others, and have produced multiple stroma-related transcriptomic data sets now in the public domain. We developed novel technologies for implanting stromal cells in human artificial lymph nodes and for seeding stromal cells onto solid substrates, designed to determine the impact of topography on stromal cell function, and developed machine learning algorithms and high-throughput image analysis to assess the effect of varying surface geometry. We have extended imaging modalities to study stromal in high resolution and in multiple dimensions, and developed approaches to study their mechanical properties.
In the thematic area of stromal cells and lymphoid tissue development and organisation, we discovered that adhesion molecule expression was heavily influenced by surface topography. We identified a novel link between the structural and functional adaptability of stromal cells with mechanical stress. We discovered that stromal cell re-organisation during LN hypertrophy induced by adjuvant-containing vaccines was regulated by a complex cytokine cascade. We have made important new discoveries on the lineage relationships between stromal cell subsets, including showing that splenic white pulp stromal cells arise from a common α-SMA+ progenitor. Our research has led to a reassessment of the role of mesenchymal lymphoid tissue organizer cells in SLO development. We identified new links between stromal cells and innate lymphoid cells. We identified expression of the neuroregulatory receptor RET in ILC3s, and identified lamina propria stromal cells as a potent source of RET ligands. We conducted gene profiling on human fetal LN stromal cells and innate lymphoid cells from LN and tonsils, identifying the breadth of pattern recognition receptor expression on these cells.
In the thematic area of infection, cancer and inflammation, we developed new tools to identify human stromal cell subsets, using these for the study of follicular lymphoma (FL) niches. We developed a new in vivo xenograft model and discovered that CXCL12 overexpression regulated by IL-4 could contributes to FL recruitment and should be considered as a new therapeutic target. Conversely, loss of CXCL12 was discovered to be one of the underlying mechanisms controlling the partial bone marrow failure observed in the parasitic disease visceral leishmaniasis. The collateral damage resulting from local IFNγ production also damages the hematopoietic stem cell pool. Our data suggest new therapeutic approaches to restoring bone marrow function in this globally important infectious disease. Using pre-clinical cancer models, we have begun to identify optimal modalities for the use of combination therapies targeting both T cell activation (e.g. PD-L1) and the tumour-associated vasculature. Finally, we discovered that stromal reticular cells activate lymphatic endothelial cells via RANKL, opening new opportunities for RANKL as a target in the treatment of chronic inflammatory and autoimmune diseases.
In summary, STROMA has generated new understanding of this important class of cells, helping to elevate them from their position as mere scaffolds underpinning immune architecture into cells with well-recognised and important immunoregulatory functions. The tools and methodologies developed in STROMA are being widely distributed across the scientific community and will fuel further academic, commercial and translational opportunities over the coming years.