Abstract
Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.
Highlights
The adaptive immune system undergoes a severe and systemic decline in proper function with age, resulting in higher susceptibility to a wide range of infections and decreased efficacy of vaccination in elderly individuals (Ademokun, Wu, and Dunn-Walters 2010; Kogut et al 2012; Dunn-Walters and Ademokun 2010)
To investigate the effect of age on the B-cell receptor repertoire diversity and composition in turquoise killifish, we implemented an RNA-based repertoire-sequencing protocol based on the published protocol of Turchaninova et al (Turchaninova et al 2016), using template switching (Zajac et al 2013) to add unique molecular identifiers (UMIs) to each RNA transcript of the immunoglobulin heavy chain (Figure 1) (Bradshaw and Valenzano 2020) to correct for errors and biases in abundance arising during PCR and Illumina sequencing (Vollmers et al 2013)
The turquoise killifish is the shortest-lived vertebrate that can be bred in captivity (Cellerino, Valenzano, and Reichard 2016; Harel and Brunet 2015), with a median lifespan in the short-lived GRZ strain of about four months
Summary
The adaptive immune system undergoes a severe and systemic decline in proper function with age, resulting in higher susceptibility to a wide range of infections and decreased efficacy of vaccination in elderly individuals (Ademokun, Wu, and Dunn-Walters 2010; Kogut et al 2012; Dunn-Walters and Ademokun 2010). In the humoral immune system, aging is accompanied by a decline in naïve B cell output from the primary lymphoid organs; impaired production of specific antibodies in response to antigenic challenge; and a decline in antibody quality (Ademokun, Wu, and Dunn-Walters 2010; Kogut et al 2012; Sasaki et al 2011; Aberle et al 2013), as well as impairments in the establishment of novel immune memory (Aberle et al 2013) These changes are major contributors to a generalized immunosenescent phenotype that significantly impairs health and quality of life in the elderly. While within-individual repertoire diversity declines with age, between-individual variability increases, with repertoires from older individuals differing 60 more from one another than those from young individuals (de Bourcy et al 2017)
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