Anergic/suppressive CD4+CD25+ T cells exist in animal models but their presence has not yet been demonstrated in humans. We have identified and characterized a human CD4+CD25+ T cell subset, which constitutes 7–10 % of CD4+ T cells in peripheral blood and tonsil. These cells are a CD45RO+CD45RBlow highly differentiated primedT cell population that is anergic to stimulation. Depletion of this small subset from CD4+ T cells significantly enhances proliferation by threefold in the remaining CD4+CD25– T cells, while the addition of isolated CD4+CD25+ T cells to CD4+CD25– T cells significantly inhibits proliferative activity. Blocking experiments suggest that suppression is not mediated via IL‐4, IL‐10 or TGF‐β and is cell‐contact dependent. Isolated CD4+CD25+ T cells are susceptible to apoptosis that is associated with low Bcl‐2 expression, but this death can be prevented by IL‐2 or fibroblast‐secreted IFN‐β. However, the anergic/suppressive state of these cells is maintained after cytokine rescue. These human regulatory cells are therefore a naturally occurring, highly suppressive, apoptosis‐prone population which are at a late stage of differentiation. Further studies into their role in normal and pathological situations in humans are clearly essential.

Anergic/suppressive CD4+CD25+ T cells have been proposed to play an important role in the maintenance of peripheral tolerance. Here we demonstrate that in humans these cells suppress proliferation to self antigens, but also to dietary and foreign antigens. The suppressive CD4+CD25+ T cells display a broad usage of the T cell receptor Vβ repertoire,suggesting that they recognize a wide variety of antigens. They reside in the primed/memory CD4+CD45RO+CD45RBlow subset and have short telomeres, indicating that these cells have the phenotype of highly differentiated CD4+ T cells that have experienced repeated episodes of antigen‐specific stimulation in vivo. This suggests that anergic/suppressiveCD4+CD25+ T cells may be generated in the periphery as a consequence of repeated antigenic encounter. This is supported by the observation that highly differentiated CD4+T cells can be induced to become anergic/suppressive when stimulated by antigen presented by non‐professional antigen‐presenting cells. We suggest that besides being generated in the thymus, CD4+CD25+ regulatory T cells may also be generated in the periphery. This would provide a mechanism for the generation of regulatory cells that induce tolerance to a wide array of antigens that may not be encountered in the thymus.

No abstract

Intraspecific variation may be continuous, or it may be quantized, if the number of structures present is always an integer. If there is some modal number of structures present in almost all individuals, variation is said to be modal. A developmental process is defined as one of ‘simple quantization’ if, first, it gives rise to an integral number of structures, and secondly, if the number of structures formed depends on the ratio between two continuous variables, for example the field size and the chemical wavelength in the model suggested by Turing (1952). Whether variation is quantized or modal will then depend on the accuracy with which these continuous variables are regulated. The larger the modal number, the more accurate must this regulation be. Data on the range of continuous variation within animal populations sug­gest that simple quantization cannot give rise to modal numbers greater than about 5 to 7. Yet modal numbers of 30 or more occur. Three processes which might account for this dis­crepancy are suggested, and evidence is presented to show that two of them occur. These are ‘multiplicative’ processes, involving successive processes of simple quantization, and ‘chemical counting’ processes, depending on qualitative differences between successively formed structures. The relevance of processes of quantization to the genesis of two-dimensional patterns is discussed.

No abstract

No abstract

No abstract

No abstract