Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice (original) (raw)
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A nondeletional mechanism of peripheral tolerance in T-cell receptor transgenic mice
Proceedings of the National Academy of Sciences, 1991
To investigate tolerance to extrathymic self molecules, we produced two groups of trsn m : one expressed the major histocompatibility complex molecule H-2Kb in pancreatic P cells, and the other expeed rearranged T-cell receptor genes encoding an and-H-2Kb receptor. The trMsgenic T-cell receptor genes were shown to confer the correct specificity and to be ex T cells bearing this receptor were activated by H2Kb us vitro and in ivo, and they underwent negative selection in mice e g H_2Kb in the thymus. To determine the fate and fction of
Using a transgenic (Tg) model, we demonstrate that although alloantigen (Ag)-specific TCR-3'//~ cells are deleted in the thymus and spleen of Ag-bearing mice, intraepithelial lymphocytes (IELs) expressing normal levels of the Tg TCR were present. However, Tg + IELs from Agbearing mice were unresponsive to activation. Furthermore, self-reactive Tg + IELs decreased in number over time. Thus, in epithelial tissue, Tg TCR-3,//~ cells are eliminated subsequent to and most likely as a result of the induction of clonal anergy. C lonal deletion of immature self-reactive TCR-a/fl cells is the major intrathymic mechanism for the maintenance of T cell tolerance (1-7). Self-reactive peripheral TCR-a/fl cells that escape thymic donal deletion or encounter antigen in the periphery can be rendered unresponsive by clonal anergy (8-15) or be eliminated in the periphery (16, 17). However, less is known about the maintenance of self-tolerance among TCK-3,//~ cells. These T cells, which comprise a small subset of T cells in peripheral lymphoid tissue, predominate in epithelial linings of the skin, intestine, lung, and reproductive organs (18). To examine self-tolerance in TCK-3,/6 cells, we generated transgenic (Tg) 1 mice expressing an alloreactive TCK~/~ Earlier studies demonstrated that Tg TCK-'),/~ cells localizing to peripheral lymphoid tissue in alloantigen (Ag)bearing mice were deleted in the thymus (19). In the present study, we examined tolerance of Tg TCR-3,//~ intraepithelial lymphocytes (IELs) in Ag-bearing H-2 b mice. Matcriah and Methods Animals. Adult H-2 a/a and H-2 b/a normal and transgenic mice (Tg a/a and Tg b/a) were generated by the cross of a Tg a/a (founder no. 75 • BALB/c)F1 male (19) to either C57BL/10 or BALB/c females. Mice were raised in conventional conditions in the University of Chicago Carlson animal facility.
Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver
European Journal of Immunology, 1995
By transgenic expression of ovalbumin (OVA) as a model self antigen in the  cells of the pancreas, we have shown that self tolerance can be maintained by the cross-presentation of this antigen on dendritic cells in the draining lymph nodes. Such cross-presentation causes initial activation of OVA-specific CD8 T cells, which proliferate but are ultimately deleted; a process referred to as cross-tolerance. Here, we investigated the molecular basis of cross-tolerance. Deletion of CD8 T cells was prevented by overexpression of Bcl-2, indicating that cross-tolerance was mediated by a Bcl-2 inhibitable pathway. Recently, Bim, a pro-apoptotic Bcl-2 family member whose function can be inhibited by Bcl-2, was found to play a critical role in the deletion of autoreactive thymocytes, leading us to examine its role in cross-tolerance. Bim-deficient T cells were not deleted in response to cross-presented self-antigen, strongly implicating Bim as the pro-apoptotic mediator of cross-tolerance. * Abbreviations used in this paper: AICD, activation-induced cell death; CFSE, carboxy fluorescein diacetate succinimidyl ester; DC, dendritic cell; ␥ c, common ␥ chain cytokine receptor; mOVA, membrane-bound ovalbumin; RIP, rat insulin promoter; SEB, staphylococcus enterotoxin B.
Proceedings of the National Academy of Sciences, 1989
To examine the effects of aberrant expression ofclass H major histocompatibility complex (MHC) proteins on tolerance development, transgenic mice expressing the I-Al genes under control of the pancreatic elastase promoter were produced. Such transgenic mice express I-Ad exclusively on exocrine pancreas, without expression in thymus or by lymphocytes. No spontaneous development of autoimmune reactivity toward exocrine pancreas was found in transgeneexpressing mice of an H-2b background even though such mice could produce in vitro allogeneic responses against I-Ad. When T cells from nontransgenic H-2b mice as well as transgenic H-2b mice were activated in vitro by I-Ad allogeneic stimulator cells and transferred to transgenic mice, an intense, destructive lymphocytic infiltrate specific for exocrine pancreas developed. These findings suggest that aberrant class II MHC expression alone may not trigger autoimmune reactions. Rather, the unresponsiveness to allogeneic class II MHC may result from the inability of exocrine pancreas to initiate primary responses by T cells.
Journal of Experimental Medicine, 1992
To study the role of thymic education on the development of the human T cell repertoire, SCIDhu mice were constructed with fetal liver and fetal thymus obtained from the same or two different donors. These animals were studied between 7 and 12 mo after transplantation, at which times all thymocytes and peripheral T cells were derived from stem cells of the fetal liver graft. Immunohistology of the thymus grafts demonstrated that thymic epithelial cells were of fetal thymus donor (FTD) origin. Dendritic cells and macrophages of fetal liver donor (FLD) origin were abundantly present in the medullary and cortico-medullary areas. Thymocytes of SCID-hu mice transplanted with liver and thymus of two different donors (FLDA/FTDB animals) were nonresponsive to Epstein-Barr virus-transformed B cell lines (B-LCL) established from both the FLDA and FTDB, but proliferated vigorously when stimulated with third-party allogeneic B-LCL. Mixing experiments showed that the nonresponsiveness to FTDB was not due to suppression. Limiting dilution analysis revealed that T cells reacting with the human histocompatibility leukocyte antigens (HLA) of the FLD were undetectable in the CD8 + T cell population and barely measurable in the CD4 + subset. On the other hand, CD4 + and CD8 + T cells reactive to the HLA antigens of the FTD were readily detectable. These results indicate that FLD-reactive cells were clonally deleted, whereas FTD-reactive cells were not. However, the frequencies of FTD-reactive T cells were consistently twofold lower than those of T cells specific for any third-party B-LCL. In addition, the cytotoxic activity and interleukin 2 production by FTD-specific T cells were lower compared with that of third-party-reactive T cell clones, suggesting that FTD-specific cells are anergic. These data demonstrate that T cells become tolerant to autologous and allogeneic HLA antigens expressed in the thymus via two different mechanisms: hematopoietic cells present in the thymus induce tolerance to "self"-antigens by clonal deletion, whereas thymic epithelial cells induce tolerance by clonal anergy and possibly deletion of high affinity clones. J. Exp.
Limited capacity for tolerization of CD4+ T cells specific for a pancreatic ? cell neo-antigen
Immunity, 1995
Mice transgenic for SV40 T antigen (Tag) under control of the rat insulin promoter (RIP) develop two altemative immunological phenotypes: tolerance or autoimmunity towards Tag. We utlllzed the T cell receptor (TCR) genes expressed in a Tag-specific CD4+ cell from an autoimmune RIP-Tag mouse to generate two lines of TCR transgenic mice in which either 10% or 90% of peripheral T cells express the transgenic TCR. When cross-bred to the tolerant RIPl-Tag2 line, mice from the low frequency TCR line showed partlal dela tlon of peripheral Tag-specific T cells and nonresponsiveness of those that remained. In contrast, crossbred mice in which transgenlc T cells comprlaed a majority of the T cell population were nontolerant both in vivo and in vitro. Thus, tolerkation of CD4+ T cells specific for a mre self-antigen may fail if too many autoreactive T cells develop.