Transient Depletion of Dividing T Lymphocytes In Mice Induces the Emergence of Regulatory T cells and Dominant Tolerance to Islet Allografts
Résumé
We previously showed that transient depletion of dividing T cells at the time of an allogeneic transplantation induces long‐term tolerance to the allograft. Here we investigated the role of homeostatic perturbation and regulatory T cells (Treg) in such tolerance. Transient depletion of dividing T cells was induced at the time of an allogeneic pancreatic islets graft, by administration of ganciclovir for 14 days, into diabetic transgenic mice expressing a thymidine kinase (TK) conditional suicide gene in T cells. Allograft tolerance was obtained in 63% of treated mice. It was not due to global immunosuppression, permanent deletion or anergy of donor‐alloantigens specific T cells but to a dominant tolerance process since lymphocytes from tolerant mice could transfer tolerance to naïve allografted recipients. The transient depletion of dividing T cells induces a 2‐ to 3‐fold increase in the proportion of CD4+CD25+Foxp3+ Treg, within 3 weeks that persisted only in allograft‐bearing mice but not in nongrafted mice. Tolerance with similar increased proportion of Treg cells was also obtained after a cytostatic hydroxyurea treatment in normal mice. Thus, the transient depletion of dividing T cells represents a novel means of immuno‐intervention based on disturbance of T‐cell homeostasis and subsequent increase in Treg proportion.
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