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Autoimmune diseases are more represented in Down syndrome (DS) individuals compared to chromosomally normal people. Natural T regulatory cells (nTreg) have been considered to be primary in the role of controlling the intensity and targets of the immune response. We have investigated the phenotypical and functional alteration of nTreg in a group of DS people. The phenotypical characteristic of Treg cells of 29 DS was analysed and compared with an age-matched healthy control group. The inhibitory potential of CD4+CD25highCD127low T regulatory cells was evaluated on autologous CD4+CD25- T cell proliferation in response to activation with a mytogenic pan-stimulus (anti-CD2, anti-CD3 and anti-CD28 antibodies). The CD4+CD25high cells in the DS and control groups were 2·692 ± 0·3808%, n = 29 and 1·246 ± 0·119, n = 29%, respectively ( P = 0.0007), with a percentage of forkhead box protein 3 (FoxP3)-expressing cells of 79·21 ± 3·376%, n = 29 and 59·75 ± 4·496%, respectively ( P = 0.0015). CD4+CD25+FoxP3+ cells were increased in peripheral blood from DS subjects (DS mean 5·231 ± 0·6065% n = 29, control mean 3·076 ± 0·3140% n = 29). The majority of CD4+CD25high were CD127low and expressed a high percentage of FoxP3 (natural Treg phenotype). While the proliferative capacity of DS T cells was not altered significantly compared to normal individuals, a reduced inhibitory potential of Treg compared to healthy controls was clearly observed (mean healthy control inhibition in Teff : Treg 1:1 co-culture: 58·9% ± 4·157%, n = 10 versus mean DS inhibition in Teff : Treg 1:1 co-culture: 39·8 ± 4·788%, n = 10, P = 0.0075; mean healthy control inhibition in Teff : Treg 1:0·5 co-culture: 45·10 ± 5·858%, n = 10 versus DS inhibition in Teff : Treg 1:0·5 co-culture: 24·10 ± 5·517%, n = 10, P = 0.0177). DS people present an over-expressed peripheral nTreg population with a defective inhibitory activity that may partially explain the increased frequency of autoimmune disease. [ABSTRACT FROM AUTHOR]