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Defining the Requirements for Peptide Recognition in Gene Therapy-Induced T Cell Tolerance¹

Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129

Expression of a retrovirally transduced MHC class I Ag, H-2K^b (K^b), in bone marrow-derived cells leads to specific prolongation of K^b disparate skin grafts. To examine the extent to which peptides derived from K^b contribute to the induction of tolerance, retroviruses carrying mutant K^b genes designed to enter separate pathways of Ag presentation were constructed. Thymectomized and CD8 T cell-depleted mice that had been irradiated and reconstituted with bone marrow cells expressing a secreted form of K^b showed prolongation of K^b disparate skin graft survival. Skin graft prolongation was not observed when similar experiments were performed using mice that were not CD8 T cell depleted. This suggests that hyporesponsiveness can be induced in CD4 T cells, but not CD8 T cells by Ags presented via the exogenous pathway of Ag processing. Modest prolongation of skin allografts was observed in mice reconstituted with bone marrow cells transduced with retroviruses carrying a gene encoding a mutant K^b molecule expressed only in the cytoplasm. Prolongation was also observed in similar experiments in mice that were thymectomized and CD4 T cell depleted following complete reconstitution, but not in mice that were reconstituted and then thymectomized and CD8 T cell depleted. Thus, hyporesponsiveness can be induced in a subset of CD8 T cells by recognition of peptides derived from K^b through both the direct and indirect pathways of Ag recognition, while CD4 T cell hyporesponsiveness to MHC class I disparate grafts occurs only through the indirect pathway of Ag recognition.

This article has been cited by other articles:

				J. Bagley, C. Tian, D. H. Sachs, and J. Iacomini Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy Blood, May 29, 2002; 99(12): 4394 - 4399. [Abstract] [Full Text] [PDF]