Abnormal regulatory and effector T cell function predispose to autoimmunity following xenogeneic thymic transplantation.
Document Type
Article
Publication Date
2008
Keywords
Animals, Autoimmunity, Cell-Survival, Epithelial-Cells, Female, Mice-Inbred-BALB-C, Mice-Nude, Spleen, Swine, Swine-Miniature, T-Lymphocytes-Regulatory, Thymus-Gland, Transplantation-Immunology, Transplantation-Heterologous
First Page
7649
Last Page
7659
JAX Source
J Immunol 2008 Dec; 181(11):7649-59.
Abstract
Porcine thymus grafts support robust murine and human thymopoiesis, generating a diverse T cell repertoire that is deleted of donor and host-reactive cells, achieving specific xenograft tolerance. Positive selection is mediated exclusively by the xenogeneic thymic MHC. Although thymectomized, T cell-depleted normal mice usually remain healthy following xenogeneic thymic transplantation, thymus-grafted congenitally athymic mice frequently develop multiorgan autoimmunity. We investigated the etiology of this syndrome by adoptively transferring lymphocyte populations from fetal pig thymus-grafted BALB/c nude mice to secondary BALB/c nude recipients. Fetal pig thymus-grafted nude mice generated normal numbers of CD25(+)Foxp3(+)CD4 T cells, but these cells lacked the capacity to block autoimmunity. Moreover, thymocytes and peripheral CD4(+)CD25(-) cells from fetal pig thymus-grafted nude mice, but not those from normal mice, induced autoimmunity in nude recipients. Injection of thymic epithelial cells from normal BALB/c mice into fetal pig thymus grafts reduced autoimmunity and enhanced regulatory function of splenocytes. Our data implicate abnormalities in postthymic maturation, expansion, and/or survival of T cells positively selected by a xenogeneic MHC, as well as incomplete intrathymic deletion of thymocytes recognizing host tissue-specific Ags, in autoimmune pathogenesis. Regulatory cell function is enhanced and negative selection of host-specific thymocytes may potentially also be improved by coimplantation of recipient thymic epithelial cells in the thymus xenograft.
Recommended Citation
Fudaba Y,
Onoe T,
Chittenden M,
Shimizu A,
Shaffer JM,
Bronson R,
Sykes M.
Abnormal regulatory and effector T cell function predispose to autoimmunity following xenogeneic thymic transplantation. J Immunol 2008 Dec; 181(11):7649-59.