Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function

Garfin, Phillip M.; Nguyen, Thuyen; Sage, Julien

doi:10.1371/journal.pone.0149430

Cited by 4 publications

(1 citation statement)

References 38 publications

(38 reference statements)

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“…The CD4/CD8 profile was not altered in K18 recipients ( Fig 5Bb ) compared to that in WT recipients, suggesting that Rb-TS inactivation in K18+ TEC affected the TEC proliferation without disrupting the TEC differentiation and T cell development. This is unlike the effect of Pten deletion in TEC that loss of Pten in TEC resulted in a smaller thymus and T cell development was disturbed (increased CD8+ T cells) [ 30 ]. Interestingly, we found significant decrease of splenic and bone marrow B220+ cells in K18 recipients compared to WT recipients ( S4B Fig ), which might explain why spleen weight was not changed although splenic CD4+ and CD8+ cells were increased in induced- K18 mice.…”

Section: Resultsmentioning

confidence: 99%

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

et al. 2017

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Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size.

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Section: Resultsmentioning

confidence: 99%

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

et al. 2017

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Germline PTEN mutations are associated with a skewed peripheral immune repertoire in humans and mice

Jaini

Loya

King

et al. 2020

Human Molecular Genetics

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Individuals with germline mutations in the gene encoding Phosphatase and Tensin Homolog on chromosome Ten (PTEN) are diagnosed with PTEN Tumor Hamartoma Syndrome (PHTS) and are at high risk for developing breast, thyroid and other cancers and/or autoimmunity or neurodevelopmental issues including autism spectrum disorders (ASD). Although well recognized as a tumor suppressor, involvement of PTEN mutations in mediating such a diverse range of phenotypes indicates a more central involvement for PTEN in immunity than previously recognized. To address this, sequencing of the T-cell receptor variable-region β-chain (TCRVB) was performed on peripheral blood from PHTS patients. Based on patient findings, we performed mechanistic studies in two Pten knock-in murine models, distinct from each other in cell compartment-specific predominance of Pten. We found that PTEN mutations in humans and mice are associated with a skewed T- and B-cell gene repertoire, characterized by increased prevalence of high frequency clones. Immunological characterization showed that Pten mutants have increased B-cell proliferation and a proclivity towards increased T-cell reactivity upon Toll-like-receptor stimulation. Furthermore, decreases in nuclear but not cytoplasmic Pten levels associated with a reduction in expression of the Autoimmune Regulator (Aire), a critical mediator of central immune tolerance. Mechanistically, we show that nuclear PTEN most likely regulates Aire expression via its emerging role in splicing regulation. We conclude that germline disruption of PTEN, both in human and mouse, results in compromised central immune tolerance processes that may significantly impact individual stress-responses and therefore predisposition to autoimmunity and cancer.

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Changes in expression of special AT-rich sequence binding protein 1 and phosphatase and tensin homologue in kidneys of diabetic rats during ageing

Jukic

Kostić

Filipović

et al. 2018

Nephrology Dialysis Transplantation

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Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function

Cited by 4 publications

References 38 publications

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

Germline PTEN mutations are associated with a skewed peripheral immune repertoire in humans and mice

Changes in expression of special AT-rich sequence binding protein 1 and phosphatase and tensin homologue in kidneys of diabetic rats during ageing

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