It is conceivable that a combination of at least two events, intrathymic and peripheral, may combine to create the phenotype observed in CD25 deficiency. First, there is a potentially inefficient negative selection process rooted in abnormal thymic differentiation, as evidenced in the failure to express CD1 and to regulate bcl-2. Second, there may be an inability to control potential autoreactive cells in the periphery because of the absence of the CD25⁺ CD4⁺ T-cell subset.⁴³ Inefficient activation-induced cell death, as observed in the CD25 knockout mouse,¹⁵ also may contribute to the phenotype observed. The lack of CD25 expression also may compromise the ability of peripheral T cells to proliferate after stimulation and thus result in the profound immunodeficiency observed.