Inborn errors of immunity associated with defects of thymic development

Abstract

The main function of the thymus is to support the establishment of a wide repertoire of T lymphocytes capable of eliminating foreign pathogens, yet tolerant to self-antigens. Thymocyte development in the thymus is dependent on the interaction with thymic stromal cells, a complex mixture of cells comprising thymic epithelial cells (TEC), mesenchymal and endothelial cells. The exchange of signals between stromal cells and thymocytes is referred to as "thymic cross-talk". Genetic defects affecting either side of this interaction result in defects in thymic development that ultimately lead to a decreased output of T lymphocytes to the periphery. In the present review, we aim at providing a summary of inborn errors of immunity (IEI) characterized by T-cell lymphopenia due to defects of the thymic stroma, or to hematopoietic-intrinsic defects of T-cell development, with a special focus on recently discovered disorders. Additionally, we review the novel diagnostic tools developed to discover and study new genetic causes of IEI due to defects in thymic development. Finally, we discuss therapeutic approaches to correct thymic defects that are currently available, in addition to potential novel therapies that could be applied in the future.

Keywords: T-cell lymphopenia; immune deficiency; inborn errors of immunity; thymic development; thymic stroma; thymus.

FIGURE 1

Figure shows known players involved in thymus organogenensis, TEC development and function. PA, pharyngeal pouch; TEC, thymic epithelial cell. Created with BioRe nder.com.

FIGURE 2

Schematic view of thymocyte development from the bone marrow to the thymic cortex and medulla. Blunt arrows identify developmental blocks in various forms of ibron errors of immunity due to hematopoietic gene defects. BM HSC, bone marrow hematopoietic stem cell; DP, double positive; ETP, early thymic progenitor; SP, single positive. Created with BioRe nder.com.