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.

Keywords: BMP4; IL-22; T cell reconstitution; endogenous thymic regeneration; immune restoration; thymic epithelial cells.

Figure 1

Therapeutic approaches for boosting thymus function. Regenerative therapies to boost thymic function after acute damage or to reverse age-related involution can be broadly stratified into four subgroups based on their cellular or molecular targets: (1) targeting the epithelial microenvironment that supports thymopoiesis; (2) targeting the precursors that provide the supply of developing thymocytes; (3) modulation of hormones and metabolism; and (4) cellular therapies and bioengineering. However, within each of these therapeutic modalities there are key nexus points at which they act mechanistically. One approach relies on stimulating TEC function, such as IL-22, BMP4, KGF, RANKL, SSI, which act by either promoting survival, proliferation, differentiation, or expression of key thymopoietic molecules like DLL4 and KITL. In contrast, approaches such as administration of exogenous IL-7 and chemokine therapies target T cell precursors to promote their migration, proliferation, and differentiation directly. Similarly, many of the bioengineering approaches have sought to recapitulate these same functions such as providing TEC signals or a ready supply of T cell precursors. Elements of the figure were generated using Biorender.com.