1. Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence
- Author
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Elif Karakoc Aydine, Helen C. Su, John C. Pascall, Ann Y Park, Safa Baris, Silvia Vilarinho, Jahnavi Aluri, Aaron Morawski, Yu Zhang, Lixin Zheng, Rick P. Lifton, V. Koneti Rao, Sinan Sari, Ahmet Ozen, Helen F. Matthews, Brittany Chao, Isil Barlan, Xijin Xu, Michael Leney-Greene, Ping Jiang, Michael J. Lenardo, Geoff W. Butcher, Matthew Lynberg, and Ayca Kiykim
- Subjects
Senescence ,Lymphocyte ,Spleen ,Disease ,mTORC1 ,Biology ,medicine.disease ,medicine.disease_cause ,Autoimmunity ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,Immunodeficiency - 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 naïve 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 naïve 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.
- Published
- 2021
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