Thymic involution and immune reconstitution

Abstract

Chronic thymus involution associated with aging results in less efficient T-cell development and decreased emigration of naïve T cells to the periphery. Thymic decline in the aged is linked to increased morbidity and mortality in a wide range of clinical settings. Negative consequences of these effects on global health make it of paramount importance to understand the mechanisms driving thymic involution and homeostatic processes across the lifespan. There is growing evidence that thymus tissue is plastic and that the involution process might be therapeutically halted or reversed. We present here progress on the exploitation of thymosuppressive and thymostimulatory pathways using factors such as keratinocyte growth factor, interleukin 7 or sex steroid ablation for therapeutic thymus restoration and peripheral immune reconstitution in adults.

Figure 1

Thymic function decreases with age. (a) Top panel shows cytokeratin-immunostained and hematoxylin & eosin (H&E)-counterstained thymus sections from healthy young and aged human donors. In the aged thymus, the perivascular space (P) is increased in size and the thymopoietic cortex (C) and medulla (M) are significantly constricted. Lower panel shows flow cytometric analysis of CD4 and CD8 on thymocytes isolated from healthy young and aged human thymus donors; a clear reduction in double positive (DP) CD4⁺CD8⁺ T cells be seen in aged individuals. (b) sjTREC (single joint T-cell receptor excision circle) measurement per microgram of circulating peripheral blood mononuclear cell (PBMC) DNA from healthy human donors ranging from <1 to ∼80 years of age demonstrates a steady decline of naïve T-cell output with age. (c) Human thymus tissue from a 78-year-old female. Tissue was immunostained with anti-cytokeratin and H&E counterstained to show remaining islands of cortical and medullary tissue (blue). (d) Islands of cortical and medullary tissue in aged thymus show signs of active thymopoiesis by CD1a and Ki67 immunostain.

Figure 2

Factors involved in thymic involution and reconstitution. Young thymus produces self-tolerant T cells expressing a broad T-cell receptor (TCR) repertoire, and this is supported in a well-delineated cortex and medulla by functionally distinct stromal cell populations. With age, there is a gradual reduction in total thymic cellularity, an increase in perivascular space (PVS), disruption of the thymic architecture, a reduced production of naïve T cells and a restriction in the peripheral TCR repertoire. Involution of the thymus occurs in parallel with increased production of sex steroids in humans. Treatment with thymostimulatory cytokines, such as keratinocyte growth factor (KGF), interleukin 7 (IL-7), growth hormone (GH), leptin and ghrelin, or sex steroid ablation therapy (SSA), can promote regeneration of an atrophic thymus—increasing total cellularity, restoring thymic architecture, increasing output of naïve T cells and rejuvenating the diversity of the peripheral TCR repertoire. This might occur by several mechanisms including an increase in thymus seeding by early T-lineage progenitors (ETPs) or increased proliferation and/or differentiation of triple negative (TN), double positive (DP) or single positive (SP) thymocytes.