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Modulation of Fas-Dependent Apoptosis: A Dynamic Process Controlling Both the Persistence and Death of CD4 Regulatory T Cells and Effector T Cells¹

Institut National de la Santé et de la Recherche Médicale, Unité 345, Institut Necker, Paris, France

We have previously shown that regulatory CD25⁺CD4⁺ T cells are resistant to clonal deletion induced by viral superantigen in vivo. In this work we report that isolated CD25⁺CD4⁺ T cells activated in vitro by anti-CD3 Ab are resistant to Fas-induced apoptosis, in contrast to their CD25^-CD4⁺ counterparts. Resistance of CD25⁺CD4⁺ T cells to Fas-dependent activation-induced cell death is not linked to their inability to produce IL-2 or to their ability to produce IL-10. The sensitivity of both populations to Fas-induced apoptosis can be modulated in vitro by changing the CD25⁺CD4⁺:CD25^-CD4⁺ T cell ratio. The sensitivity of CD25^-CD4⁺ T cells to apoptosis can be reduced, while the sensitivity of CD25⁺CD4⁺ T cells can be enhanced. Modulation of Fas-dependent apoptosis is associated with changes in cytokine production. However, while CD25^-CD4⁺ T cell apoptosis is highly dependent on IL-2 (production of which is inhibited by CD25⁺CD4⁺ T cells in coculture), modulation of CD25⁺CD4⁺ T cell apoptosis is IL-2 independent. Taken together, these results suggest that CD25⁺CD4⁺ and CD25^-CD4⁺ T cell sensitivity to Fas-dependent apoptosis is dynamically modulated during immune responses; this modulation appears to help maintain a permanent population of regulatory T cells required to control effector T cells.

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