RAG1
V(D)J recombination-activating protein 1 (RAG-1) (RING finger protein 74) [Includes: Endonuclease RAG1 (EC 3.1.-.-); E3 ubiquitin-protein ligase RAG1 (EC 2.3.2.27) (RING-type E3 ubiquitin transferase RAG1)] [RNF74]
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Aging is a risk factor for cardiovascular diseases and adaptive immunity has been implicated in angiotensin (Ang) II-induced target-organ dysfunction. Herein, we sought to determine the role of T-cell senescence in Ang II-induced target organ impairment and to explore the underlying mechanisms. Flow cytometric analysis revealed that T cell derived from aged mice exhibited immuno-senescence. Adoptive transfer of aged T cells to immunodeficient RAG1 KO mice accelerates Ang II-induced cardiovascular and renal fibrosis compared with young T cell transfer. Aged T cells also promote inflammatory factor expression and superoxide production in these target organs. In vivo and in vitro studies revealed that Ang II promotes IFN-γ production in the aged T cells comparing to young T cells. Importantly, transfer of senescent T cell that IFN-γ KO mitigates the impairment. Aged T cell-conditioned medium stimulates inflammatory factor expression and oxidative stress in Ang II-treated renal epithelial cells compared with young T cells, and these effects of aged T cell-conditioned medium are blunted after IFN-γ-neutralizing antibody pretreatment. These results provide a significant insight into the contribution of senescent T cells to Ang II-induced cardiovascular dysfunction and provide an attractive possibility that targeting T cell specifically might be a potential strategy to treat elderly hypertensive patients with end-organ dysfunction. Aging is a risk factor for cardiovascular diseases. Adaptive immunity has been implicated in Ang II-induced target-organ dysfunction. Here, we utilized adoptive transfer of young or aged T cell into RAG1-/- mice and provide the direct evidence that senescent T-cell was more sensitive to Ang II stimulation and exerted an adverse impact on target-organ, in which senescent T cell-derived IFN-γ may play a critical role. These findings might shed new light on the contribution of T-cell senescence to target-organ injury in age-related hypertension.
Keywords
- T cell
- angiotensin II
- cardiorenal dysfunction
- senescence
Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN. To study the quality of immune systems stemming selectively from young or aged HSCs, we established a HSC transplantation model in T- and B-cell-deficient young RAG1 hosts. We report that both phenotypic and functional changes in the immune system on aging are primarily a consequence of changes in the function of HSCs on aging and, to a large extent, independent of the thymus, as young and aged HSCs reconstituted distinct T- and B-cell subsets in RAG1 hosts that mirrored young and aged immune systems. Importantly, aged HSCs treated with CASIN reestablished an immune system similar to that of young animals, and thus capable of mounting a strong immune response to vaccination. Our studies further imply that epigenetic signatures already imprinted in aged HSCs determine the transcriptional profile and function of HSC-derived T and B cells.
MeSH Terms
- Aging
- Animals
- Cellular Senescence
- Cytoskeletal Proteins
- Female
- Gene Expression Profiling
- Genes, RAG-1
- Graft Survival
- Hematopoietic Stem Cell Transplantation
- Hematopoietic Stem Cells
- Lymphocyte Subsets
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Tissue Donors
- Vaccination
- Vaccines, DNA
- rho GTP-Binding Proteins