Dataset Information

C-Cbl deficiency leads to diminished lymphocyte development and functions in an age-dependent manner.

ABSTRACT: Aging is broadly defined as a progressive decline of tissue and organ functions due to deregulation of various cell intrinsic and extrinsic factors. In the immune system, aging preferentially affects lymphopoiesis and thus results in the reduced competence of the adaptive immune system in the elderly. Despite recent discoveries that shed light on the molecular basis of aging, pathways that lead to diminished lymphoid development in aging individuals remain largely unknown. In the present study, we document that a deficiency of the E3 ubiquitin ligase c-Cbl in lymphocytes results in an age-dependent lymphopenia. c-Cbl-deficient mice show normal frequencies of lymphocytes at 12 weeks of age; however, their development and functions were remarkably diminished at 24 weeks after birth. Intriguingly, c-Cbl mutant lymphocytes displayed increased responses to IL7 in vitro and failed to down-regulate surface levels of IL7Ralpha. Further, our biochemical studies have identified an interaction of c-Cbl with IL7Ralpha and have unraveled the involvement of c-Cbl in the ubiquitylation of IL7Ralpha. In essence, our studies demonstrate that a lack of signaling events mediated by c-Cbl might result in diminished lymphocyte development and functions, particularly, at the later stages of life.

SUBMITTER: Rathinam C

PROVIDER: S-EPMC2889568 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

c-Cbl deficiency leads to diminished lymphocyte development and functions in an age-dependent manner.

Rathinam Chozhavendan C Flavell Richard A RA

Proceedings of the National Academy of Sciences of the United States of America 20100419 18

Aging is broadly defined as a progressive decline of tissue and organ functions due to deregulation of various cell intrinsic and extrinsic factors. In the immune system, aging preferentially affects lymphopoiesis and thus results in the reduced competence of the adaptive immune system in the elderly. Despite recent discoveries that shed light on the molecular basis of aging, pathways that lead to diminished lymphoid development in aging individuals remain largely unknown. In the present study, ...[more]

PMID: 20404156

Similar Datasets

Project description:Pathogenic variants of the gene Eda cause X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by structural abnormalities or lack of ectodermal appendages. Signs of dysplasia are not restricted to derivatives of the ectodermal layer, but mesodermal abnormalities, such as craniofacial dysmorphism, are also frequently observed, suggesting close reciprocal interactions between the ectoderm and mesoderm; however, a causal link has remained unsubstantiated. We investigated the functional impact of defective ectodysplasin A1 (Eda1) signaling on postnatal bone homeostasis in Eda1-deficient Tabby mice. Interestingly, Eda1 was detected in wild-type mouse calvariae throughout postnatal lifetime. In calvariae, bone-lining Osterix (Osx)+ osteoblasts stained positive for Eda1, and osteoclasts were revealed as Eda receptor (Edar)-positive. Moreover, adult Eda1-deficient calvarial bone showed osteopetrosis-like changes with significantly diminished marrow space, which was maintained during adulthood. Concomitantly with osteopetrosis-like changes, Tabby calvarial bone and Tabby bone marrow-derived osteoclasts had far less osteoclastic activity-associated co-enzymes including cathepsin K, Mmp9, Trap, and Tcirg1 (V-type proton ATPase a3 subunit) compared with wild-type calvariae in vivo or osteoclasts in vitro, indicating that Eda1 deficiency may affect the activity of osteoclasts. Finally, we confirmed that nuclear Nfatc1-positive osteoclasts were strongly diminished during mature osteoclastic differentiation under M-CSF and RANKL in the Tabby model, while Fc-EDA treatment of Tabby-derived osteoclasts significantly increased nuclear translocation of Nfatc1. Furthermore, we identified enhanced Nfatc1 and NF-κB transcriptional activity following Fc-EDA treatment in vitro using luciferase assays. Overall, the results indicate that diminished expressions of osteoclastic activity-associated co-enzymes may lead to disturbed bone homeostasis in Tabby calvariae postnatally.

Dataset Information

C-Cbl deficiency leads to diminished lymphocyte development and functions in an age-dependent manner.

Publications

c-Cbl deficiency leads to diminished lymphocyte development and functions in an age-dependent manner.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets