Abnormal regulatory and effector T cell function predispose to autoimmunity following xenogeneic thymic transplantation.
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.
Fudaba
Yasuhiro
Y
Department of Surgery, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Onoe
Takashi
T
Chittenden
Meredith
M
Shimizu
Akira
A
Shaffer
Juanita M
JM
Bronson
Roderick
R
Sykes
Megan
M
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D002470:Cell Survival / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000637:transplantation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013154:Spleen / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology / Q000637:transplantation*; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous