The existence of a population of unique regulatory T cells was rekindled following a series of experiments that involved the neonatal thymectomy of mice. Thymectomy on day 3 after birth led to the development of a wide spectrum of organ-specific autoimmune diseases, whereas delaying thymectomy to day 7 after birth abrogated this problem. On the basis of these findings it was assumed that a population of regulatory T cells develops later in life than autoimmune effector cells, and that thymectomy on day 3 prevented selectively the emigration of such regulatory T cells.75 Given what is known now about establishment of the peripheral T-cell pool and homeostatic mechanisms, there are alternative interpretations for the observed phenomena and it is doubtful that they indeed prove the existence of a subpopulation of T cells which is generated in the thymus and dedicated to the job of immune regulation. For instance, it is clear that the peripheral immune system of neonatal mice contains very few T lymphocytes and can therefore be considered lymphopenic (Fig. 2). Adult numbers of T cells are not reached until day 7 in the lymph nodes and day 15 in the spleen.76 As a consequence, naïve T cells proliferate and acquire the phenotype and function of activated/memory T cells,47,48 an effect that requires self-peptide/MHC interactions and is regulated by the size of the peripheral T-cell pool. In the absence of continuous thymic output, such T cells can expand to the same extent as T cells adoptively transferred into T-cell-deficient hosts. This has serious implications for the functionality of the immune system. Loss of the naïve T-cell pool as a result of homeostatic imbalances in lymphopenia causes selective outgrowth of oligoclonal populations which differ between individual mice and often cause immune pathology, or even autoimmunity.77,78 There are various other experimental manipulations of mice where lymphopenia results in the development of organ-specific autoimmunity, such as neonatal administration of cyclosporin, high-dose fractionated total lymphoid irradiation and single-chain TCR transgenic mice (reviewed in ref. 79). T-cell depletion, leading to partial lymphopenia, can also result from a number of clinical conditions, such as chemotherapy, radiation, or treatment with cyclosporin A, and many viral or bacterial infections cause substantial lymphopenia.80–84