Human Thymic Involution and Aging in Humanized Mice

Abstract

Thymic involution is an important factor leading to the aging of the immune system. Most of what we know regarding thymic aging comes from mouse models, and the nature of the thymic aging process in humans remains largely unexplored due to the lack of a model system that permits longitudinal studies of human thymic involution. In this study, we sought to explore the potential to examine human thymic involution in humanized mice, constructed by transplantation of fetal human thymus and CD34 + hematopoietic stem/progenitor cells into immunodeficient mice. In these humanized mice, the human thymic graft first underwent acute recoverable involution caused presumably by transplantation stress, followed by an age-related chronic form of involution. Although both the early recoverable and later age-related thymic involution were associated with a decrease in thymic epithelial cells and recent thymic emigrants, only the latter was associated with an increase in adipose tissue mass in the thymus. Furthermore, human thymic grafts showed a dramatic reduction in FOXN1 and AIRE expression by 10 weeks post-transplantation. This study indicates that human thymus retains its intrinsic mechanisms of aging and susceptibility to stress-induced involution when transplanted into immunodeficient mice, offering a potentially useful in vivo model to study human thymic involution and to test therapeutic interventions.

Immune ageing at single-cell resolution

“…CD4 + T cells Decreased abundance of naive cells in the blood 60,61,137,138 Increased abundance of T EM cells in the blood 138 Decreased abundance of recent thymic emigrants in the blood 137 Decreased abundance of an interferon-activated subset in the blood 25 Increased abundance of the cytotoxic subset in the blood (supercentenarians) 72 scRNA-seq, flow cytometry CD8 + T cells Decreased abundance of naive cells in the blood 25,61,138 Increased abundance of T EM cells in the blood 25,138 Increased abundance of the GZMK + (CD28 + CD57 -) subset of T EM cells in the blood 25 Increased abundance of the CD57 + subset in the blood 149 scRNA-seq, flow cytometry, mass cytometry features of exhausted CD8 + T cells. Exhausted-like CD4 + T cells constitute about 30% of all CD4 + T cells in the spleen of aged mice.…”

“…For example, monocytes increase in abundance whereas plasmacytoid dendritic cells decrease in abundance in both species when they age 25,135,136 . Similarly, naive CD4 + T cells and CD8 + T cells and populations of SOX4-expressing γδ T cells are less abundant in old mice and humans 25,137,138 . Furthermore, cytotoxic CD4 + T cells and GZMK + CD8 + T EM cells universally accumulate during ageing in both species 25,69,72 .…”

Ectopic cervical thymi and no thymic involution until midlife in naked mole rats

“…In vertebrates, aging of the thymus gland precedes age‐associated phenotypic changes in other organs, with thymic function gradually decreasing from the first year of human life (Shanley et al, 2009 ). The process of human thymic involution is incompletely understood, in part due to a lack of animal models showing delayed immunosenescence (Tong et al, 2020 ).…”

Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons

“…Prior studies indicate that age is negatively associated with naïve CD4+CD31+ proportions in healthy individuals (11,22,23). We therefore evaluated the relation between age and naïve CD4 cells here, and determined if HCV treatment state impacted the relationship between age and naïve CD4+, CD4+CD31+ and CD4+CD31-counts and proportions in our cross-sectional cohort.…”