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Abnormal Regulatory and Effector T Cell Function Predispose to Autoimmunity following Xenogeneic Thymic Transplantation¹

Yasuhiro Fudaba^2,*, Takashi Onoe^*, Meredith Chittenden^*, Akira Shimizu^*, Juanita M. Shaffer^*, Roderick Bronson and Megan Sykes^3,*

^* Department of Surgery, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129; and Department of Pathology, Harvard Medical School, Boston, MA 02114

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants P01 AI045897 and P01 HL18646, Juvenile Diabetes Research Foundation Basic Science Grant 1-2007-723, and Immerge BT. Y.F. was supported in part by the Uehara Memorial Foundation. T.O. was supported in part by a Postdoctoral Fellowship for Research of Abroad from the Japan Society for the Promotion of Science.

² Current address: Second Department of Surgery, Hiroshima University, Faculty of Medicine, 1-2-3 Kasumi Minami-ku, Hiroshima 734-8551, Japan.

³ Address correspondence and reprint requests to Dr. Megan Sykes, Transplantation Biology Research Center, Massachusetts General Hospital, Massachusetts General Hospital East Building 149-5102, 13th Street, Boston, MA 02129. E-mail address: megan.sykes{at}tbrc.mgh.harvard.edu

⁴ Abbreviations used in this paper: ATX, thymectomized; FP, fetal pig; THY, thymus; FPG, FP THY-grafted; FP THY/LIV, FP THY and liver tissue; GSPL, splenocytes from FPG mice; nSPL, normal splenocytes; LN, lymph node; FCM, flow cytometry; Treg, regulatory T cell; mTEC, murine thymic epithelial cell.

⁵ The online version of this article contains supplemental material.