Primary and secondary defects of the thymus

Abstract

The thymus is the primary site of T-cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non-self, whilst remaining tolerant to self- antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self-renewal capacity decreases with age. Secondary and age-related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age-related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects.

Keywords: AIRE; DiGeorge syndrome; FOXN1; T-cell reconstitution; athymia; immune restoration; immunodeficiency; immunosenescence; thymic atrophy; thymic epithelial cells; thymic involution; thymic regeneration; thymopoiesis; thymus; thymus transplantation.

Fig. 1:. Causes for primary and secondary defects of the thymus.

Primary thymic defects are cause genetically (red). Secondary defects can be due to intrauterine exposure to adverse conditions (green), or can arise postnatally following clinical interventions, diseases, or malnutrition (yellow). Prenatal, postnatal and age-related thymic hypofunction can have the same consequences with great variety in severity and persistance. A self-reinforcing cycle is possible in which primary or secondary defects of the thymus, e.g. secondary to cytoreductive therapy for HSCT, lead to clinical conditions, for example infections or acute GVHD, that, in turn, may aggravate thymic dysfunction, thereby increasing the risk for further clinical consequences, for example chronic autoimmune phenomena. PP, pharyngeal pouch; HSCT, hematopoietic stem cell transplantation; endog., endogeneous; exog., exogeneous; TEP, thymus epithelial progenitor cell; TEC, thymus epithelial cell; GVHD, graft versus host disease; AIRE, autoimmune regulator.

Fig. 2:. Early thymus organogenesis.

(A) Development of thymic epithelial cells (TECs) in humans. From the anterior foregut endoderm, which is patterend by morphogens including retinoic acid (RA), the third pharyngeal pouch arrises. A common thymus and parathyroid primordium arises and is surrounded by mesenchymal cells derived from the neural crest ectoderm. At that time, the thymic primordium contains a bipotent thymic epithelial progenitor (TEP) cell. Lymphocytes immigrate. The primordia seperate and migrate in a BMP4 dependend manner. The two thymic primordia meet in the anterior mediastinum and form the bi-lobed organ. (B) Formation and patterning of the third pharyngeal pouch and early TEP development is regulated by a network of transcription factors. An earlier, FOXN1 indipendend phase (in the endoderm, grey box) can be distinguished from a later, stage dependend on FOXN1, the master regulator of TEC development (in TEPs, red box). The arrows interconnecting the transcription factors and indicating a hierarchy are based on murine data. All displayed transcription factors lead to severe hypo- or aplasia if knocked out in mouse models. Transcription factors annoted with a star* were reported to cause human thymus aplasia if mutated in a loss of function manner, including HOXA3 (own unpublished data) (C) The development and function of the thymic stromal and lymphocyte compartment are highly interdependent. Development and maturation of TECs and subsequent differentiation into cTECs and mTECs requires crosstalk with lymphocytes. For mTEC development, single positive αβ thymocytes that have recently undergone positive selection by cTECs provide their ligands, including RANK, CD40 and lLT-β. Thereby, mTEC maturate and express the autoimmune regulator (AIRE) and costimulatory molecules. Mature mTECs enable establishmend of central tolerance by inducing apoptosis or Treg development of self-reactive T-cell clones.

Fig. 3:. Postnatal T-cell development in humans.

Early thymic progenitors migrate from the bone marrow to the thymus and enter at the cortico-medullary junction. They lack expression of T-cell receptor (TCR), CD4 and CD8. As the thymocytes progress through subsequent Pro- and Pre-T stages and reach the immature single positive stage where they express the pre-TCR. The pre-TRC is composed of a non-rearranging pre-Tα chain and a rearranged TCR β-chain. Successful pre-TCR expression leads to excessive cell proliferation and replacement of the pre-TCR α-chain with a newly rearranged TCR α-chain, resulting in a complete αβ TCR. The DP, αβ-TCR+CD4+CD8+ expressing thymocytes then interact with MHC class I and class II (MHC-I, MHC-II) molecules associated with self-peptides on cortical thymic epithelial cells (cTEC). The survival of the DPs depends on signaling that is mediated by interaction of the TCR with these self-peptide–MHC ligands. Low signaling leads to apoptosis. An intermediate level of TCR signaling enables further maturation (positive selection). Thymocytes that express TCRs that bind self-peptide–MHC -I complexes become CD8+ T-cells, whereas those that express TCRs that bind self-peptide–MHC-II ligands become CD4+ T-cells. During negative selection, occurring mostoly in the medulla where medullary thymic epithelial cells (mTECs), dendritic cells and B-cells present tissue restricted antigens (TRAs), too much signaling promotes apoptosis or generation of regulatory T-cells (Treg). Mature T-cells emigrate to the circulation. HSC, hematopoietic stem cell.

Fig. 4:. Selected endogeneous and exogeneous mechanisms of thymic regeneration in humans.

Involved factors are assigned to the producing cell type, either from the thymic stromal compartment (yellow) or from the thymocyte compartment (blue). Arrows indicate the target cells. Factors in pink were administered in clinical trials.