Thymus Degeneration and Regeneration

Abstract

The immune system's ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus's development, factors causing thymic injury, and the strategies for improving thymus regeneration.

Keywords: autoimmune; degeneration; regeneration; thymic epithelial cells; thymus.

Figure 1

Illustration of factors causing thymic injury. The thymus is a delicate organ sensitive to insults, including chemotherapeutic drugs, corticosteroids, radiation, and pathogens. Allo-HSCT treatment regime and its complications (GVHD) likewise have detrimental effects on the thymocytes. Age-dependent thymic atrophy naturally occurs due to a decline in the thymus’s self-renewal capacity and subsequent accumulation of toxic substances, including free radicals.

Figure 2

Interleukin-22 promotes endogenous thymic regeneration. Exposing the thymus to infection, irradiation, and Allo-HSCT treatment regime (1) results in depletion of CD4+ CD8+ Double positive (DP) thymocytes (2) DP depletion modulates IL-23 up-regulation in dendritic cells and T cells (3). IL-23 then induces the group 3 innate lymphoid cells (ILC3) to produce IL-22 cytokines (4). IL-22 regulates AIRE and RORy(t) via JAK/STAT3/Mcl-1 pathway (5). This subsequently causes a significant increase in TEC proliferation/survival, thus boosting TEC and thymus regeneration.