Monoallelic germline TSC1 mutations are permissive for T lymphocyte development and homeostasis in tuberous sclerosis...

Germline and somatic biallelic mutations of the Tuberous sclerosis complex (TSC) 1 and TSC2 gene products cause TSC, an autosomal dominant multifocal hamartomatosis with variable neurological manifestations. The consequences of TSC1 or TSC2 loss in cells of hematopoietic origin have recently started to be unveiled in mice and showed to hinder the development of proper T cell immunity. To date, the consequences of germline TSC1 mutations and/or its loss in mature human T cells remain to be determined. To address these issues, we analyzed subset representation, phenotype and responsiveness to mitogens in T cells from patients with inherited monoallelic TSC1 mutations, and induced shRNA-mediated TSC1 down-regulation in primary and transformed human T cells. We report that, the distribution of peripheral CD4 and CD8 T cell subsets, their cytokine-secretion profile, and responsiveness to in vitro stimulation were largely preserved in TSC subjects with monoallelic TSC1 germline mutations when compared to healthy controls. Sufficient levels of hamartin and tuberin and proper control of mTOR-dependent signaling in primary T cells from TSC subjects best explained this. In contrast, shRNA-induced down-regulation of TSC1, likely mimicking biallelic inactivation of TSC1, compromised hamartin and tuberin expression and mTORC2/AKT/FoxO1/3 signaling causing both primary and transformed T cells to die by apoptosis. Thus, our results indicate that, while one functional TSC1 allele preserves human T lymphocytes development and homeostasis, TSC1 acute down-regulation is detrimental to the survival of both primary and transformed T cells.