Thymus: the next (re)generation

Abstract

As the primary site of T-cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way toward the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the preclinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.

Keywords: aging; thymus damage; tissue regeneration.

Figure 1. Targets of acute thymic damage and pathways of endogenous regeneration

The thymus is extremely sensitive to damage, typically in the form of irradiation, cytoreductive chemotherapy or stress-induced (or administered) corticosteroids. While most of these insults target the T cell progenitors (most prominently CD4+CD8+ DP thymocytes), TECs are also notably targeted by both irradiation and cytoreductive chemotherapy. Corticosteroids specifically target thymocytes and so other cell populations including TECs, dendritic cells (DCs), fibroblasts (FC), innate lymphoid cells (ILCs) and endothelial cells (ECs) are relatively untouched initially (although due to crosstalk there is a decline in the numbers of cTECs and mTECs after the thymocyte depletion). ILCs and ECs, and to a lesser extent FC and DC, are remarkably resistant to acute damage. After injury the thymus has a remarkable capacity to regenerate itself. While the mechanisms underlying this regeneration remain poorly understood, in the past few years several pathways have been revealed. These include the IL-23/IL-22 and KGF pathways, which targets TECs; IL-7, which can be produced by both TECs and FCs and target early T cell progenitors; and VEGF, which can be produced by TECs and some thymocytes and targets ECs to induce angiogenesis, a crucial step during organ regeneration.