Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

Abstract

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.

Keywords: DiGeorge syndrome; FOXN1; PAX1; primary immunodeficiency; regenerative medicine; severe combined immunodeficiency (SCID); thymus transplantation.

Figure 1

Lymphostromal crosstalk in thymic grafts. (A) Developing thymocytes communicate with antigen (Ag)-presenting cells (APC) through HLA-TCR interactions. APCs include both thymic stromal cells and hematopoietic cells. In thymic grafts these APCs can be host-derived (in blue) or donor-derived (in orange). The thymus tissue donor and the athymic patient are not HLA-matched. (B) After thymus transplantation, lymphoid progenitors migrate from the recipient’s bone marrow into the HLA-mismatched thymic graft. In the thymic cortex developing thymocytes undergo positive selection of competent T-cells through low-affinity engagement of their TCR with HLA-bound antigens. In the case of serendipitous, partial HLA-matching between donor and recipient, traditional antigen-presentation by cTECs may occur (1). Donor-derived fibroblasts (Fb) possibly also contribute to this (2). In theory, host-derived APCs of hematopoietic origin in the graft may also contribute to positive selection, for example through direct thymocyte-thymocyte interactions (3). Positively selected DP thymocytes then undergo negative selection to eliminate autoreactive T-cells. In the thymic graft this may also start in the cortex thanks to direct HLA-TCR mediated interactions with DCs of host origin (4). In normal thymus tissue generation of self-tolerance predominantly takes place in the medulla. If there is partial HLA-matching between the donor and the recipient, donor-derived mTECs and possibly fibroblasts can contribute to this in thymic grafts (5 and 6). Host-derived hematopoietic cells, in particular DCs, may also play a role (7). Additionally, it is possible that upon transplantation chimeric thymic stroma develops with stromal cells of host origin, both in the cortex and the medulla (8). Figure created with BioRender.com.