Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors.
Immune tolerance to self-antigens is established during lymphocyte differentiation in the thymus, but a simple means to induce antigen-specific tolerance in the thymus is 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 (Tregs). This positive selection increased the number of HA-specific Tregs 10-fold and was comparable with 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 Tregs 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 Tregs 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 nonobese diabetic mice. Intrathymic gene transfer using lentiviral vectors thus offers new means to manipulate antigen-specific tolerance.
Marodon
Gilles
G
Université Pierre et Marie Curie-Paris6 (UPMC), UMR 7087, Hôpital de La Pitié-Salpêtrière, Paris, France.
Fisson
Sylvain
S
Levacher
Béatrice
B
Fabre
Monique
M
Salomon
Benoît L
BL
Klatzmann
David
D
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D005434:Flow Cytometry; D005822:Genetic Vectors; D006386:Hemagglutination Tests; D006801:Humans; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D016086:Lentivirus; D017493:Leukocyte Common Antigens / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic
D053645:Interleukin-2 Receptor alpha Subunit; D017493:Leukocyte Common Antigens