Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption
Siddiqui S1, Lustig A2, Carter A2, Sankar M3, Daimon CM3, Premont RT4, Etienne H5,6, van Gastel J5,6 Azmi A5,6, Janssens J5,6, Becker KG7, Zhang Y7, Wood W7, Lehrmann E7, Martin JG8, Martin B3, Taub DD2, Maudsley S1,5,6.
The authors have no specific financial interests to disclose related to this work.
Recent research suggests that GIT2 acts as a controller of the aging process. Thymic involution is an evolutionarily conserved hallmark of the aging. Thymic involution describes an age-dependent shrinking of the thymus gland coincident with alterations in tissue architecture and fat infiltration. We investigated how GIT2deletion would affect thymic involution. At a relatively young age, 12 months old GIT2 knockout (GIT2KO) mice presented a prematurely disrupted thymic structure compared to wild-type mice. Thymic disruption was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I. Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in GIT2KO mice compared to controls. Coincident with this premature thymic disruption in GIT2KO mice was the generation of novel cervical 'organs', i.e. 'parathymic lobes' (PTLs). GIT2KO PTLs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Signaling pathway analysis of GIT2KO thymic and PTL transcriptomic data demonstrated that molecular signaling functions lost in the GIT2KO thymus were specifically reinstated in PTLs. Further analysis of transcriptomic data from GIT2KO lymph nodes, spleen, thymus and PTLs revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in cell clock regulation, senescence and DNA damage. Altered clock regulation therefore may be responsible for the premature aging phenotype of GIT2KO mice.
- Receptor Pharmacology Unit, Laboratory of Neurosciences, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA.
- Laboratory of Molecular Biology and Immunology, NIA, NIH, Baltimore, MD 21224, USA.
- Metabolism Unit, Laboratory of Clinical Investigation, NIA, NIH, Baltimore, MD 21224, USA.
- Duke University Medical Center, Durham, NC 27705, USA.
- Department of Biomedical Sciences, University of Antwerp, Belgium.
- Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
- Gene Expression and Genomics Unit, Research Resources Branch, NIA, NIH, Baltimore, MD 21224, USA.
- Research Institute of the MUHC, Centre for Translational Biology (CTB), Meakins-Christie Laboratories, McGill University, Montreal, QC, H4A 3J1, Canada.
The authors have no specific financial interests to disclose related to this work.
Recent research suggests that GIT2 acts as a controller of the aging process. Thymic involution is an evolutionarily conserved hallmark of the aging. Thymic involution describes an age-dependent shrinking of the thymus gland coincident with alterations in tissue architecture and fat infiltration. We investigated how GIT2deletion would affect thymic involution. At a relatively young age, 12 months old GIT2 knockout (GIT2KO) mice presented a prematurely disrupted thymic structure compared to wild-type mice. Thymic disruption was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I. Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in GIT2KO mice compared to controls. Coincident with this premature thymic disruption in GIT2KO mice was the generation of novel cervical 'organs', i.e. 'parathymic lobes' (PTLs). GIT2KO PTLs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Signaling pathway analysis of GIT2KO thymic and PTL transcriptomic data demonstrated that molecular signaling functions lost in the GIT2KO thymus were specifically reinstated in PTLs. Further analysis of transcriptomic data from GIT2KO lymph nodes, spleen, thymus and PTLs revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in cell clock regulation, senescence and DNA damage. Altered clock regulation therefore may be responsible for the premature aging phenotype of GIT2KO mice.
