Developmental changes of FOXP3-expressing CD4⁺CD25⁺ regulatory T cells and their impairment in patients with FOXP3 gene mutations

FOXP3 is required for the generation and function of CD4⁺CD25⁺ regulatory T (Treg) cells. To elucidate the biological role of Treg cells, we used a monoclonal anti-FOXP3 antibody to examine the frequencies of Treg cells during child development. The percentages of CD4⁺CD25⁺FOXP3⁺ T cells were constant shortly from after birth through adulthood. CD4⁺CD25⁺FOXP3⁺ T cells in cord blood showed the naive CD45RA⁺CD45RO^- phenotype, whereas adult CD4⁺CD25⁺FOXP3⁺ T cells expressed mostly the memory CD45RA^-CD45RO⁺ phenotype. The age-dependent dominance of memory CD4⁺CD25⁺FOXP3⁺ T cells implies functional differences between naive and memory Treg cells. Notably, four patients with FOXP3 gene mutations revealed a paucity of CD4⁺CD25⁺FOXP3⁺ T cells. Importantly, one patient with a frame shift mutation, who showed typical symptoms of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), exhibited marked T cell activation, whereas others with missense mutations, who were clinically milder, did not. This observation suggests a possible genotype-phenotype correlation in IPEX.