When the Damage Is Done: Injury and Repair in Thymus Function

Abstract

Even though the thymus is exquisitely sensitive to acute insults like infection, shock, or common cancer therapies such as cytoreductive chemo-or radiation-therapy, it also has a remarkable capacity for repair. This phenomenon of endogenous thymic regeneration has been known for longer even than its primary function to generate T cells, however, the underlying mechanisms controlling the process have been largely unstudied. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines with age as a function of thymic involution; which even at steady state leads to reduced capacity to respond to new pathogens, vaccines, and immunotherapy. Consequently, there is a real clinical need for strategies that can boost thymic function and enhance T cell immunity. One approach to the development of such therapies is to exploit the processes of endogenous thymic regeneration into novel pharmacologic strategies to boost T cell reconstitution in clinical settings of immune depletion such as HCT. In this review, we will highlight recent work that has revealed the mechanisms by which the thymus is capable of repairing itself and how this knowledge is being used to develop novel therapies to boost immune function.

Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development

“…Based on the success of long-sought observations in histology and embryology, recent progress in and applications of single-cell transcriptome technologies have unveiled the functional diversity of such non-TEC stromal cells and highlighted their immunological functions. Along with pioneering studies on the regeneration of TECs ( 128 – 131 ), a better understanding of the cellular and molecular basis of the entire set of thymic stromal cells will provide valuable insights toward the in vivo reconstitution of the thymus for future therapeutic applications.…”

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease

“…In addition to the everyday insults like stress and infection, the thymus is also exquisitely sensitive to cytoreductive therapies like chemotherapy and radiation, often used in the conditioning required for successful hematopoietic cell transplant (HCT) [ 13 , 14 ]. In mouse models, studies have found that after both total body irradiation (TBI) or chemotherapy, in addition to the direct depletion of highly proliferative thymocytes, there is significant damage to the nonhematopoietic epithelial microenvironment resulting in reduced T cell development [ 15 , 16 ]; which may result from the relatively high rate of turnover of some TEC subsets [ 17 ]. Although damage and recovery are worse in older individuals whose thymus has already undergone significant involution, prolonged T cell depletion after cytoreductive therapies can be dangerous in even relatively young individuals; which has been shown in cohorts of human patients [ 18 ] and in mice [ 19 , 20 ].…”

“…One approach used to identify therapeutic strategies to boost thymic function has been to exploit the mechanisms that govern endogenous regeneration from acute injury [ 16 ]. As described above, studies have found that IL-22, KGF, RANKL, and BMP4 are all involved in the endogenous response to injury, and all can be utilized to boost thymic function in the setting of acute damage [ 77 , 88 , 95 , 96 ].…”

In Pursuit of Adult Progenitors of Thymic Epithelial Cells

“…The thymus is extremely sensitive to damage and exposure to acute or chronic insults results in a pronounced decline in cellularity, a phenomenon known as thymic atrophy ( 41 , 42 ). For example, we recently demonstrated thymic atrophy displayed by mice under microgravity (0 g) conditions during spaceflight, which was partially mitigated by exposure to 1 g during spaceflight ( 43 ).…”

“…For example, we recently demonstrated thymic atrophy displayed by mice under microgravity (0 g) conditions during spaceflight, which was partially mitigated by exposure to 1 g during spaceflight ( 43 ). After resolution of acute insults such as infections, cytoreductive therapies, and emotional and physical discomfort, the thymus is able to regenerate, although its capacity declines with age ( 41 , 42 ). To study this endogenous thymic regeneration, researchers have employed viral and bacterial infections, sub-lethal irradiation, and synthetic corticosteroid injections to model acute insults ( 44 – 50 ).…”