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"Dissecting the human T cell response to pathogens, allergens, and self-antigens"

Final Report Summary - PREDICT (Dissecting the human T cell response to pathogens, allergens, and self-antigens)

The research project PREDICT focused on T lymphocytes, a cell type that is a key player in the immune system, controlling essentially all aspects of immune responses. The project aimed at deciphering the T cell response that protects the host from infection by viruses, bacteria or fungi, but also that causes pathology when reacting against environmental antigens, such as in allergy, or self-antigens, such as in autoimmunity. Within the PREDICT project, we combined methods of next generation sequencing with in vitro stimulation and analysis of specific T cells, to establish for the first time a complete catalogue of the immune response to two important human pathogens, Candida albicans and Mycobacterium tuberculosis. Using this new approach, we could rapidly decipher the language of T lymphocytes, that is, their identity, specificity and function, and could do it for the thousands of clones that mediate the immune response against these pathogens. In this way, we discovered that when a naive T cell recognizes a pathogen and proliferates in order to eradicate it, the progeny cells may undergo different fates, such as acquiring the ability to produce different types of cytokines or to migrate to different tissues. This extreme flexibility of T lymphocytes represents a new element that explains how the human immune system is able to respond to attacks with different weapons and on several fronts. Within PREDICT we also collaborated with neurology departments to study a neurological disorder called narcolepsy. Patients with narcolepsy suffer of excessive daytime sleepiness and brief episodes of loss of muscle tone triggered by emotions. The disease was known to be caused by the loss of a protein in the brain called hypocretin, and to develop in genetically predisposed individuals, but the underlying mechanism remained mysterious. Our study demonstrated the existence in patients with narcolepsy of autoreactive T lymphocytes that recognize hypocretin and can mediate an immune response leading to loss or hypocretin-producing neurons. The study identifies the culprit of this enigmatic disease and has major implications for its diagnosis and therapy.