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

Abstract:  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.