FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency
leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe
combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several
newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia
at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal
analysis showed persistent T cell lymphopenia during infancy, often associated with
nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases
normal CD4 + but lower than normal CD8 + cell counts. We hypothesized a FOXN1
gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis
and postulated that these effects would be more prominent early in life. To test this
hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor
(ETP) cell count, and expression of FOXN1 target genes ( Ccl25 , Cxcl12 , Dll4 ,
Scf , Psmb11 , Prss16 , and Cd83 ) in Foxn1 nu/+ ( nu/+ ) mice and age-matched
wild-type ( +/+ ) littermate controls. Both the frequency and the absolute count of
ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the
TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation
of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1
gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an
important genetic determinant of T cell lymphopenia at birth.