Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence

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 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.

The GIMAP Family Proteins: An Incomplete Puzzle

“…Lenardo's group (42) identified 4 different family clusters with mutations in GIMAP5 gene. Similar to what was reported in rats (31), GIMAP5 exists as 2 distinct isoforms in humans (42). GIMAP5 expression was observed in NK and T cells but not in B cells or monocytes.…”

“…T cells from the patients recapitulate the spontaneous mTORC1 activation observed in GIMAP5 mutant T cells from rats and mice (34). Similar to the in vitro findings (34), Gimap5 Sph/Sph mice that received rapamycin, showed reduced activation of the mTORC1 pathway (42). Treatment of one of the patients with rapamycin for over 6 years diminished splenomegaly and lymphadenopathy, suggesting aberrant activation of the AKT/mTORC1 pathway in vivo in humans in the absence of functional GIMAP5.…”

“…GIMAP5 deficient T cells also display reduced IL-7-induced STAT5 phosphorylation. It is unclear how GIMAP5 impacts the TCR and IL-7R signaling pathways and regulates AKT activity (29,34,(40)(41)(42).…”

GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

“…1 , Table 1 , and Table S1 ). Notably, all four mutations (p.I47T, p.P109L, p.L204P, and p.L223F) lead to loss of GIMAP5 protein expression, as shown in Patterson et al (2018) and Park et al (2021 Preprint ).…”