Research Paper Volume 9, Issue 3 pp 706—740
Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption
- 1 Receptor Pharmacology Unit, Laboratory of Neurosciences, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA
- 2 Laboratory of Molecular Biology and Immunology, NIA, NIH, Baltimore, MD 21224, USA
- 3 Metabolism Unit, Laboratory of Clinical Investigation, NIA, NIH, Baltimore, MD 21224, USA
- 4 Duke University Medical Center, Durham, NC 27705, USA
- 5 Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium
- 6 Gene Expression and Genomics Unit, Research Resources Branch, NIA, NIH, Baltimore, MD 21224, USA
- 7 Research Institute of the MUHC, Centre for Translational Biology (CTB), Meakins-Christie Laboratories, McGill University, Montreal, QC, H4A 3J1, Canada
Received: July 20, 2016 Accepted: February 19, 2017 Published: March 4, 2017
https://doi.org/10.18632/aging.101185How to Cite
Abstract
Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of ‘neurometabolic’ integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2-/- mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2-/- (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical ‘organ’, i.e. ‘parathymic lobes’. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe – suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature ‘aging’ phenotype of GIT2KO mice.