Our results favor a model whereby the proper suppression of colitis induced by depletion of Treg cells is only reached when three conditions are fulfilled: (i) numerically widening of CD4+CD25−Foxp3− naïve T cell source; (ii) B cell-licensed peripheral generation of CD4+CD25+Foxp3+ pTregs and (iii) presence of residual CD4+CD25−Foxp3+ thymic-derived Treg cells. This evidence concerns the gene CD4 and colitis.