Induction of alloreactive CD4 T cell tolerance in molecular chimeras: a possible role for regulatory T cells.
Induction of molecular chimerism following reconstitution of mice with autologous bone marrow cells expressing a retrovirally encoded allogeneic MHC class I Ag results in donor-specific tolerance. To investigate the mechanism by which CD4 T cells that recognize allogeneic MHC class I through the indirect pathway of Ag presentation are rendered tolerant in molecular chimeras, transgenic mice expressing a TCR on CD4 T cells specific for peptides derived from K(b) were used. CD4 T cells expressing the transgenic TCR were detected in mice reconstituted with bone marrow cells transduced with retroviruses carrying the gene encoding H-2K(b), albeit detection was at lower levels than in mice receiving mock-transduced bone marrow. Despite the presence of CD4 T cells expressing an alloreactive TCR, mice receiving H-2K(b)-transduced bone marrow permanently accepted K(b) disparate skin grafts. CD4+CD25+ T cells from mice reconstituted with H-2K(b)-transduced bone marrow prevented rejection of K(b) disparate skin grafts when adoptively transferred into immunodeficient mice along with effector T cells, suggesting that induction of molecular chimerism leads to the generation of donor specific regulatory T cells, which may be involved in preventing alloreactive CD4 T cell responses that lead to rejection.
Forman
Daron
D
Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
Kang
Eun-Suk
ES
Tian
Chaorui
C
Paez-Cortez
Jesus
J
Iacomini
John
J
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D017690:Cell Transplantation; D002478:Cells, Cultured; D002678:Chimera / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D007108:Immune Tolerance / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000378:metabolism; D014184:Transplantation, Homologous
D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell