title: Role of tumor suppressor TSC1 in regulating antigen-specific primary and memory CD8 T cell responses to bacterial infection.
abstract: The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) integrates various environmental cues such as the presence of antigen, inflammation, and nutrients to regulate T cell growth, metabolism, and function. The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of an mTOR-containing multiprotein complex called mTOR complex 1. Recent studies have revealed an essential cell-intrinsic role for TSC1 in T cell survival, quiescence, and mitochondrial homeostasis. Given the emerging role of mTOR activity in the regulation of the quantity and quality of CD8 T cell responses, in this study, we examine the role of its suppressor, TSC1, in the regulation of antigen-specific primary and memory CD8 T cell responses to bacterial infection. Using an established model system of transgenic CD8 cell adoptive transfer and challenge with Listeria monocytogenes expressing a cognate antigen, we found that TSC1 deficiency impairs antigen-specific CD8 T cell responses, resulting in weak expansion, exaggerated contraction, and poor memory generation. Poor expansion of TSC1-deficient cells was associated with defects in survival and proliferation in vivo, while enhanced contraction was correlated with an increased ratio of short-lived effectors to memory precursors in the effector cell population. This perturbation of effector-memory differentiation was concomitant with decreased expression of eomesodermin among activated TSC1 knockout cells. Upon competitive adoptive transfer with wild-type counterparts and antigen rechallenge, TSC1-deficient memory cells showed moderate defects in expansion but not cytokine production. Taken together, these findings provide direct evidence of a CD8 T cell-intrinsic role for TSC1 in the regulation of antigen-specific primary and memory responses.
authors.affiliation: Department of Pediatrics-Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, USA Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Department of Pediatrics-Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Jialong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pediatrics-Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, USA Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pediatrics-Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, USA Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA zhong001@mc.duke.edu.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D016923:Cell Death; D005786:Gene Expression Regulation / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology / Q000378:metabolism*; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D010047:Ovalbumin