Functional recreation of age-related CD8 T cells in young mice identifies drivers of aging- and human-specific tissue pathology

• Published in: Mechanisms of ageing and development 2020-10, Vol.191, p.111351-111351, Article 111351
• Main Authors: Panwar, Akanksha, Jhun, Michelle, Rentsendorj, Altan, Mardiros, Armen, Cordner, Ryan, Birch, Kurtis, Yeager, Nicole, Duvall, Gretchen, Golchian, David, Koronyo-Hamaoui, Maya, Cohen, Robert M., Ley, Eric, Black, Keith L., Wheeler, Christopher J.
• Format: Article
• Language: English
• Subjects: CD8 T cell; Cellular immunity; Homeostatic expansion; Immune aging; Neurodegeneration; Resident memory T cell
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2020.111351

•Expansion of CD8 T cells in nude mice recreates age-related phenotype, function.•Expanded CD8 T cells are reactive to self antigen and accumulate in tissue.•Persistence of expanded CD8 T cells in brain requires T cell lytic function.•Expanded CD8 T cells elicit tissue pathology of aging in skin, brain in nude hosts.•Expanded CD8 T cells humanize pathological response to brain injury in wild-type hosts. Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.