Our findings show that, in a condition where the peripheral number of tTreg has been severely diminished, the prevention of colitis requires the concerted action of three central elements: B lymphocytes, an enlarged pool of conventional CD4+CD25−Foxp3− T cells (the source of pTreg) and residual CD4+CD25−Foxp3+ tTregs. Here, CD4 is linked to colitis.