title: Human FOXN1-deficiency is associated with αβ double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon thymic transplantation.
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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Albuquerque
authors.forename: José G
authors.initials: JG
authors.lastname: Marques
authors.forename: Susana L
authors.initials: SL
authors.lastname: Silva
authors.forename: Dario
authors.initials: D
authors.lastname: Ligeiro
authors.forename: Blythe H
authors.initials: BH
authors.lastname: Devlin
authors.forename: Jacques
authors.initials: J
authors.lastname: Dutrieux
authors.forename: Rémi
authors.initials: R
authors.lastname: Cheynier
authors.forename: Claudio
authors.initials: C
authors.lastname: Pignata
authors.forename: Rui M M
authors.initials: RM
authors.lastname: Victorino
authors.forename: M Louise
authors.initials: ML
authors.lastname: Markert
authors.forename: Ana E
authors.initials: AE
authors.lastname: Sousa
mesh_terms: D000505:Alopecia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D060168:Thymocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C090140:Whn protein