Induction of Central Deletional T Cell Tolerance by Gene Therapy

Abstract

Transgenic mice expressing an alloreactive TCR specific for the MHC class I Ag Kb were used to examine the mechanism by which genetic engineering of bone marrow induces T cell tolerance. Reconstitution of lethally irradiated mice with bone marrow infected with retroviruses carrying the MHC class I gene H-2Kb resulted in lifelong expression of Kb on bone marrow-derived cells. While CD8 T cells expressing the transgenic TCR developed in control mice reconstituted with mock-transduced bone marrow, CD8 T cells expressing the transgenic TCR failed to develop in mice reconstituted with H-2Kb transduced bone marrow. Analysis of transgene-expressing CD8 T cells in the thymus and periphery of reconstituted mice revealed that CD8 T cells expressing the transgenic TCR underwent negative selection in the thymus of mice reconstituted with Kb transduced bone marrow. Negative selection induced by gene therapy resulted in tolerance to Kb. Thus, genetic engineering of bone marrow can be used to alter T cell education in the thymus by inducing negative selection.