Abstract
Forkhead box N1 (FOXN1) is a transcription factor crucial for thymic epithelium development and prevention of its involution. Investigation of a patient with a rare homozygous FOXN1 mutation (R255X), leading to alopecia universalis and thymus aplasia, unexpectedly revealed non-maternal circulating T-cells, and, strikingly, large numbers of aberrant double-negative αβ T-cells (CD4negCD8neg, DN) and regulatory-like T-cells. These data raise the possibility that a thymic rudiment persisted, allowing T-cell development, albeit with disturbances in positive/negative selection, as suggested by DN and FoxP3+ cell expansions. Although regulatory-like T-cell numbers normalized following HLA-mismatched thymic transplantation, the αβDN subset persisted 5 years post-transplantation. Involution of thymus allograft likely occurred 3 years post-transplantation based on sj/βTREC ratio, which estimates intrathymic precursor T-cell divisions and, consequently, thymic explant output. Nevertheless, functional immune-competence was sustained, providing new insights for the design of immunological reconstitution strategies based on thymic transplantation, with potential applications in other clinical settings.
Highlights
The thymus is a primary lymphoid organ essential for normal T-cell development
We identified the same homozygous R255X mutation [7,9,10], in a Portuguese child, who presented at 5 months with total alopecia and Bacillus Calmette-Guerin (BCG) dissemination, following routine neonatal vaccination with this live-attenuated mycobacterium, that presented with a significant pool of circulating non-maternal T-cells [11]
Our findings suggest that T-cell development can occur in a putative forkhead box N1 (FOXN1)-deficient thymus rudiment, albeit with altered positive and negative selection as suggested by the marked expansion of T-cells expressing the alpha-beta T-cell receptor (TCR) in the absence of both CD4 and CD8 expression together with an over-representation of T-cells of a regulatory-like phenotype expressing high levels of FoxP3 in conjunction with other regulatory markers
Summary
The unique ability of the thymic microenvironment to generate and select T-cells requires a specialized epithelium that is regulated by forkhead box N1 (FOXN1) [1,2,3,4]. This transcription factor is expressed by the thymic anlage that emanates from the epithelium of the pharyngeal pouch, and is required for the differentiation of thymic epithelial cells [1,2]. Mutations in FOXN1 lead to athymia together with total alopecia, due to the additional role of FOXN1 in hair follicle differentiation [1,2,6]
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