HUMAN TSLP · Functional characterization of the novel human cytokine TSLP and its role in health and disease

Final Activity Report Summary - HUMAN TSLP (Functional characterization of the novel human cytokine TSLP and its role in health and disease)

The immune system is essential to protect leaving organisms from microbial pathogens. Cytokines are small molecules that are involved in the regulation of immune responses. They act as a communication code between different immune cell types. Their action needs to be tightly coordinated: when appropriate, they help in our immune defence; when excessive or unregulated, they can promote inflammatory diseases, allergies or auto-immunity. Thymic stromal lymphopoietin (TSLP) is a recently discovered cytokine and thus constitutes an emerging area of research in immunology. It is produced by epithelial, stromal and mast cells. It functions by activating myeloid CD11c+ dendritic cells (DC), which subsequently modulate the T cell immune response. The biology and disease association of human TSLP remain largely unknown. The objectives of our research project were to study the role of human TSLP in the immune system and in the pathophysiology of immune-related diseases using three different approaches: 1) Study of TSLP-activated CD11c+ DC and their interaction with T cells; 2) molecular characterization of TSLP function using large-scale transcriptional analysis of TSLP-activated cells, and study of selected TSLP-induced genes in terms of expression profile, regulation and function; 3) Assessment of the in situ production of TSLP by immuno-histology in a broad array of diseases. During the project's four year duration, our studies led to novel findings with important biomedical implications. We found how keratinocytes of the skin can be induced to make TSLP, which subsequently activated DC-mediated immune response. We demonstrated that TSLP-activated DC could inhibit the Th17 pathway of immune responses. This constitutes an important link between TSLP and auto-immunity. We also identified TSLP production in psoriasis and studies are on-going to clarify the role of TSLP in this disease. Last, we found an unsuspected link between TSLP and human Papillomavirus infection (HPV). HPV is the causal agent of uterine cervical cancer and the presence of TSLP opens novel perspectives for our understanding of HPV physiopathology. We are investigating the role of TSLP as a prognostic marker that can be used for the clinical management of HPV lesions. From a more basic scientific side, we identified a novel function of TSLP in inducing migration of human DC. Thus TSLP can induce movement of cells in the body and promote immune responses. Last, molecular studies are on-going to characterise the pathways triggered by TSLP in human DC. In summary, our EXT project was very successful and identified many novel functions of human TSLP. It led to clinical studies in skin inflammation, viral infections, and cancer. TSLP and/or TSLP-induced molecules could serve as diagnostic/prognostic markers or constitute new therapeutic targets. There is no doubt that the continuation of all these projects will bring more biomedical advances in the near future. The constitution of a European pole of excellence for the study of human TSLP will increase the attractiveness and competitiveness of European research in immunology and related fields.

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