Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice

Abstract

An effective immune system depends upon the survival of mature T cells in the periphery. Members of the GIMAP family of GTPases have been proposed to regulate this homeostasis, supported by the paucity of peripheral T cells in rodents deficient for either GIMAP1 or GIMAP5. It is unclear whether this lack of T cells is a consequence of an ontological defect, causing the thymus to generate and export T cells incapable of surviving in the periphery, or whether (alternatively or additionally) mature T cells intrinsically require GIMAP1 for survival. Using the ERT2Cre+ transgene, we conditionally deleted Gimap1 in C57BL/6 mice and demonstrate that GIMAP1 is intrinsically required for the survival of mature T cells in the periphery. We show that, in contrast to GIMAP5, this requirement is independent of the T‐cells' activation status. We investigated the nature of the survival defect in GIMAP1‐deficient CD4+ T cells and show that the death occurring after GIMAP1 ablation is accompanied by mitochondrial depolarization and activation of the extrinsic apoptotic pathway. This study shows that GIMAP1 is critical for maintaining the peripheral T‐cell pool in mice and offers a potent target for the treatment of T‐cell‐mediated diseases.

TAL1-mediated epigenetic modifications down-regulate the expression of GIMAP family in non-small cell lung cancer

“…In this study, we used the TCGA and GEO databases to report down-regulation of hGIMAPs in NLCSC and analyzed that low expression of all seven GIMAP genes was associated with poor prognosis, which is consistent with shiao et al [13]. GIMAPs are generally considered to be T cell receptor stress molecules and function primarily to exert anti-apoptotic effects in the immune system [14][15][16]. The current study found that GIMAPs are present in exosomes and significantly down-regulated in the PBMC cells of lung cancer patients [17][18][19].…”

GIMAP6 is required for T cell maintenance and efficient autophagy in mice

“…Studies of rats carrying a natural mutation of the Gimap5 gene [ 11 , 12 , 42 , 43 ] and mice carrying targeted or chemically-induced mutations of the orthologous gene [ 13 , 14 ] have shown that it is required for the establishment/maintenance of normal T and (to a lesser extent) B cell lymphocyte populations. Similarly, mice carrying a targeted mutation of the Gimap1 gene in the lymphoid lineages lack T cells [ 17 , 44 ], although in this case there seems to be an equally strong effect on B cells [ 36 ]. A third membrane-anchored member of the family (GIMAP3) has also been demonstrated to be involved in T cell maintenance, although only when also linked to inactivation of GIMAP5 [ 18 ].…”

“…However in contrast to GIMAPs 3, 4 and 5 reported on by Nitta and co-workers [ 7 ], Ho and colleagues were unable to demonstrate an interaction of GIMAP6 with any obvious apoptosis-associated protein, raising the possibility that GIMAP6 may be inducing apoptosis by a distinct route. This possibility has been strengthened by genetic and cellular studies of the lymphopenias and cell death associated with GIMAP5 and GIMAP1 deficiencies [ 14 , 36 , 44 ] which cast doubt on the involvement of the BCL2-related apoptotic machinery in the lymphopenias.…”

Systemic analyses of expression patterns and clinical features for GIMAPs family members in lung adenocarcinoma

“…And the execution of programmed cell death directly correlates with the phosphorylation status of GIMAP4 [ 22 ]. Datta P et al also reported that GIMAP1 ablation is accompanied by activation of the extrinsic apoptotic pathway [ 23 ]. Given that pathway and Reactome analyses of GIMAPs, it is likely that GIMAPs are involved in molecular pathogenesis of cancer via regulation of apoptosis.…”