Submitted March 17, 2006
Accepted June 15, 2006
Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors
Gilles Marodon, Sylvain Fisson, Beatrice Levacher, Monique Fabre, Benoit L Salomon, and David Klatzmann*
Universite Pierre et Marie Curie-Paris6 (UPMC), UMR 7087, Hopital de La Pitie-Salpetriere, Paris
Departement de Pathologie, Universite de Medecine Paris-Sud, Hopital de Bicetre, France
* Corresponding author; email: david.klatzmann{at}chups.jussieu.fr.
Immune tolerance to self-antigens is established during lymphocyte differentiation in the thymus. A simple mean to induce antigen-specific tolerance in the thymus is however still elusive. We show here that intrathymic injection of a lentiviral vector expressing the hemagglutinin antigen (HA) in TCR-HA transgenic mice resulted in negative selection of HA-specific effector T-cells and sustained positive selection of HA-specific regulatory T-cells (Treg). This positive selection increased the number of HA-specific Treg by ten-fold and was comparable to the one observed in TCR-HA transgenic mice crossed with transgenic mice expressing HA under the control of the insulin promoter (Ins-HA). HA expression by radioresistant thymic epithelial cells was sufficient to drive Treg generation. Intrathymic injection of the lentiviral vector also resulted in an enrichment of HA-specific Treg cells in peripheral lymphoid organs, which prevented diabetes induced in Ins-HA mice by transfer of HA-specific effector T-cells. In this model, HA-specific Treg cells inhibited effector T-cell division in pancreatic lymph nodes. Finally, we show that intrathymic injection of a lentiviral vector expressing preproinsulin-2 could reduce the occurrence of spontaneous diabetes in non-obese diabetic mice. Intrathymic gene transfer using lentiviral vectors thus offers new means to manipulate antigen-specific tolerance.
