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Role of Themis1, a new T cell signaling protein, in normal and pathological immune responses

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A novel player in T cell responses

Many immune-related diseases are caused by impaired or aberrant T cell function. Understanding T cell signalling is a major challenge for determining the aetiology of human pathologies and developing specific therapies.

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A critical component of the immunological response to foreign protein is the activation of T lymphocytes. This takes place through the recognition of peptide-loaded major histocompatibility (MHC) molecules by the T-cell receptor (TCR) that initiates a series of downstream signalling events. The outcome of this complex signalling network is the activation and differentiation of T cells into subsets with specific and adapted immune function. The quality, duration and the strength of these signals are paramount to T cell responses and critical for discriminating between self and foreign antigens, and thus, controlling pathological disorders. Based on this, the EU-funded THEMIS project investigated the signalling events that occur downstream of the TCR and influence physiological or pathological immune responses. Researchers generated genetically modified mice deficient in the signalling molecule THEMIS, and analysed the molecular mechanism of T cell responses. Their work showed a critical role for this protein during T cell development in the thymus and in enhancing TCR signalling during positive selection. Experiments provided important information on the structure, regulation and molecular interaction of this protein with other protein partners. Further insight was obtained regarding the role of THEMIS2 in B cell development, while an additional protein, Lis1, known for its role in neuronal migration was discovered to play a critical part in T cell development. Recent evidence suggests a susceptibility role for THEMIS in multiple sclerosis and inflammatory bowel disease, although its precise role in the emergence of these pathologies has not been elucidated. Future work on THEMIS protein in these diseases will clarify if it is a direct effect of impaired T cell function or a secondary effect due to the decreased numbers of T cells in lymphoid organs. Nonetheless, the THEMIS protein is emerging as a new actor in T cell function and may serve as a novel therapeutic target in immune-mediated diseases.


T cell, TCR, THEMIS, Lis1, multiple sclerosis

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