title: Monoallelic germline TSC1 mutations are permissive for T lymphocyte development and homeostasis in tuberous sclerosis complex individuals.
abstract: 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.
authors.affiliation: Lymphocyte Activation Unit, Immunology, Transplantation and Infectious Disease Division, San Raffaele Scientific Institute, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pilipow
authors.affiliation: Lymphocyte Activation Unit, Immunology, Transplantation and Infectious Disease Division, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, and Medical Genetics, Azienda Ospedaliero-Universitaria San Giovanni Battista, Torino, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Migone
authors.affiliation: Lymphocyte Activation Unit, Immunology, Transplantation and Infectious Disease Division, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020868:Gene Silencing; D018095:Germ-Line Mutation; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000276:immunology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases