Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence

Park, A. Y.; Leney-Greene, M.; Lynberg, M.; Xu, X.; Zheng, L.; Zhang, Y.; Matthews, H.; Chao, B.; Morawski, A.; Jiang, P.; Aluri, J.; Aydine, E. K.; Kiykim, A.; Pascall, J.; Barlan, I.; Sari, S.; Butcher, G.; Rao, V. K.; Lifton, R. P.; Baris, S.; Ozen, A.; Vilarinho, S.; Su, H.; Lenardo, M. J.

doi:10.1101/2021.02.22.432146

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bioRxiv · 10.1101/2021.02.22.432146

Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence

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Abstract

Elucidating the molecular basis of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. Here we report 10 affected individuals from 4 families with a new immunodeficiency disease comprising of severe progressive lymphopenia, autoimmunity, immunodeficiency, and liver disease due to recessive loss of function variants in "GTPase of immunity-associated proteins" protein 5 (GIMAP5). We show that the disease involves the progressive loss of naive T lymphocytes and a corresponding increase in antigen-experienced, but poorly functional and replicatively senescent T cells. In vivo treatment of Gimap5-deficient mice with rapamycin (an inhibitor of mTORC1) significantly restores the fraction of naive T lymphocytes. Furthermore, a GIMAP5-deficient human patient who was treated with rapamycin (sirolimus) showed a remarkable reduction in spleen/lymph node size. Together, these observations reveal that GIMAP5 plays a critical role in lymphocyte metabolism which is essential for senescence prevention and immune competence, suggesting that an inhibitor of mTORC1 could be a valuable clinical intervention in treating patients deficient for GIMAP5.

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Park, A. Y., Leney-Greene, M., Lynberg, M., Xu, X., Zheng, L., Zhang, Y., Matthews, H., Chao, B., Morawski, A., Jiang, P., Aluri, J., Aydine, E. K., Kiykim, A., Pascall, J., Barlan, I., Sari, S., Butcher, G., Rao, V. K., Lifton, R. P., Baris, S., Ozen, A., Vilarinho, S., Su, H., Lenardo, M. J.. 2021-02-23. Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence. https://doi.org/10.1101/2021.02.22.432146

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