Abnormal Regulatory and Effector T Cell Function Predispose to Autoimmunity Following Xenogeneic Thymic Transplantation

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2008 Nov 20

PMID 19017953

Citations 14

Authors

Yasuhiro Fudaba

Takashi Onoe

Meredith Chittenden

Akira Shimizu

Juanita M Shaffer

Roderick Bronson

Megan Sykes

Affiliations

Soon will be listed here.

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.

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