T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features

Abstract

Combined Immunodeficiencies (CID) are rare congenital disorders characterized by defective T-cell development that may be associated with B- and NK-cell deficiency. They are usually due to alterations in genes expressed in hematopoietic precursors but in few cases, they are caused by impaired thymic development. Athymia was classically associated with DiGeorge Syndrome due to TBX1 gene haploinsufficiency. Other genes, implicated in thymic organogenesis include FOXN1, associated with Nude SCID syndrome, PAX1, associated with Otofaciocervical Syndrome type 2, and CHD7, one of the genes implicated in CHARGE syndrome. More recently, chromosome 2p11.2 microdeletion, causing FOXI3 haploinsufficiency, has been identified in 5 families with impaired thymus development. In this review, we will summarize the main genetic, clinical, and immunological features related to the abovementioned gene mutations. We will also focus on different therapeutic approaches to treat SCID in these patients.

Keywords: CHARGE; CHD7 gene; DiGeorge anomaly; FOXN1 gene; PAX1 gene; Pax 1/9; TBX1 gene; Thymus.

Figure 1

Genes involved in thymus organogenesis. Eya1, Six, Hoxa3, Tbx1, and Chd7 take part to the first stages of thymus development from neural crest cells (NCCs) in the posterior part of the 3rd pharyngeal pouch (PP). This step is independent from Foxn1 expression. In the second stage, Foxn1 regulates the expression of Hoxa3, Dll4, Ccl25, and Cxcl12, necessary for the thymic epithelial cells (TECs) differentiation. During this phase, cTECs (expressing K8 and K18 keratin type) and mTECs (expressing K5 and K14 keratin type) originate from the same bi-potential TECs progenitor. Chd7 is also critical for the development of cortical and medullary TECs from pharyngeal endoderm. The crosstalk between TECs and developing thymocytes is required to generate mature TECs and functional T cells.