Tolerance of class I histocompatibility antigens expressed extrathymically

Morahan, Grant; Allison, Janette; Miller, J. F. A. P.

doi:10.1038/339622a0

Cited by 237 publications

(118 citation statements)

References 12 publications

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“…Induction of T cell anergy, deletion of the autoreactive T cells usually preceded by a transient phase of activation, down-modulation of the TCR or coreceptor, and immune deviation have been described in several transgenic mice models (1)(2)(3)(4)(5)(6)(7). However, the parameters that determine the mechanisms of peripheral T cell tolerance are still fully unknown.…”

mentioning

confidence: 99%

Regulation of Activator Protein-1 and NF-κB in CD8+ T Cells Exposed To Peripheral Self-Antigens

Guerder

Rincón

Schmitt-Verhulst

2001

The Journal of Immunology

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The transcriptional events that control T cell tolerance to peripheral self Ags are still unknown. In this study, we analyzed the regulation of AP-1- and NF-κB-mediated transcription during in vivo induction of tolerance to a self Ag expressed exclusively on hepatocytes. Naive CD8+Désiré (Des)+ T cells isolated from the Des TCR-transgenic mice that are specific for the H-2Kb class I Ag were transferred into Alb-Kb-transgenic mice that express the H-2Kb Ag on hepatocytes only. Tolerance develops in these mice. We found that the self-reactive CD8+Des+ T cells were transiently activated, then became unresponsive and were further deleted. In contrast to CD8+Des+ T cells activated in vivo with APCs, which express high AP-1 and high NF-κB transcriptional activity, the unresponsive CD8+Des+ T cells expressed no AP-1 and only weak NF-κB transcriptional activity. The differences in NF-κB transcriptional activity correlated with the generation of distinct NF-κB complexes. Indeed, in vivo primed T cells predominantly express p50/p50 and p65/p50 dimers, whereas these p50-containing complexes are barely detectable in tolerant T cells that express p65- and c-Rel-containing complexes. These observations suggest that fine regulation of NF-κB complex formation may determine T cell fate.

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mentioning

confidence: 99%

Regulation of Activator Protein-1 and NF-κB in CD8+ T Cells Exposed To Peripheral Self-Antigens

Guerder

Rincón

Schmitt-Verhulst

2001

The Journal of Immunology

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“…Some investigators have reported the induction of T-cell unresponsiveness to peripherally expressed antigen (2)(3)(4)(5)(6), whereas others have found normal or near normal responsiveness (7)(8)(9)(10)(11). In those studies where functional tolerance was found, it was unclear whether autoreactive T cells were deleted or simply rendered functionally unresponsive, because it was not possible to track specific T cells in vivo.…”

mentioning

confidence: 99%

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

Fields

Loh²

1992

Proc. Natl. Acad. Sci. U.S.A.

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The developmental fate of autoreactive T cells encountering extrathymically expressed self-antigen was studied in a doubly transgenic mouse model system where pancreatic acinar cells expressed H-2Ld and T cells expressed an antigen receptor (2C TCR) specific for H-2Ld. Thymocytes bearing 2C TCR differentiated normally. They were positively selected without evidence of intrathymic clonal deletion. Survival of H12Ld-bearing skin allografts was significantly prolonged in pancreatic H-2Ld singly and doubly transgenic mice, consistent with an in vivo state of T-cell tolerance. The mechanism of tolerance induction was determined and found to have two components. First, up to 80% of peripheral CD8+2C TCR+ T cells were eliminated. Second, those T cells which escaped elimination had a signlf cantly reduced proliferative response to H-2Ld. Thus, autoreactive T cells can be made self-tolerant through interaction with self-antigen located extrathymically. This is accomplished by a reduction in the percentage of autoreactive T cells as well as by a reduction in the functional capacity of residual T cells. Surprisingly, although pancreatic lymphocytic infUltration and organ ihjury were absent in exocrine tissue of singly transgenic mice, it was present in doubly transgenic mice. This suggests that when the percentage of autoreactive T cells is high, tolerance induction can be associated with an inflammatory infiltrate in extrathymic tissue where self-antigen is presented.

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“…The absence of a lymphocytic infiltrate in the thyroid and the low level of cytotoxicity of transgenic lymphocytes to H-2Kb target cells indicates tolerance to the allogeneic class I expressed extrathymically, analogous to the ,B-cell transgenic model (1,2,27). It is possible that T cells are peripherally tolerant (27) of the transgenic alloantigen, as demonstrated for the transgenically expressed lymphocytic choriomeningitis virus glycoprotein in 1B cells (29).…”

Section: Methodsmentioning

confidence: 98%

“…It is possible that T cells are peripherally tolerant (27) of the transgenic alloantigen, as demonstrated for the transgenically expressed lymphocytic choriomeningitis virus glycoprotein in 1B cells (29). On the other hand, PCR can detect transgene mRNA in the thymus of RIP-Kb mice (25), and most importantly, tolerance to allogeneic skin grafts is acquired following transplantation of the thymus from neonatal bml RIP-Kb mice but not nontransgenic littermates to thymectomized and irradiated, bone marrow-reconstituted bml mice (21).…”

Section: Methodsmentioning

confidence: 99%

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

Frauman¹,

Chu²,

Harrison³

1993

Mol. Cell. Biol.

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The overexpression of major histocompatibility complex (MHC) class I molecules in endocrine epithelial cells is an early feature of autoimmune thyroid disease and insulin-dependent diabetes mellitus, which may reflect a cellular response, e.g., to viruses or toxins. Evidence from a transgenic model in pancreatic beta cells suggests that MHC class I overexpression could play an independent role in endocrine cell destruction. We demonstrate in this study that the transgenic overexpression of an allogeneic MHC class I protein (H-2Kb) linked to the rat thyroglobulin promoter, in H-2Kk mice homozygous for the transgene, leads to thyrocyte atrophy, hypothyroidism, growth retardation, and death. Thyrocyte atrophy occurred in the absence of lymphocytic infiltration. Tolerance to allogeneic class I was revealed by the reduced ability of primed lymphocytes from transgenic mice to lyse H-2Kb target cells in vitro. This nonimmune form of thyrocyte destruction and hypothyroidism recapitulates the beta-cell destruction and diabetes that results from transgenic overexpression of MHC class I molecules in pancreatic beta cells. Thus, we conclude that overexpression of MHC class I molecules may be a general mechanism that directly impairs endocrine epithelial cell viability.

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Tolerance of class I histocompatibility antigens expressed extrathymically

Cited by 237 publications

References 12 publications

Regulation of Activator Protein-1 and NF-κB in CD8+ T Cells Exposed To Peripheral Self-Antigens

Regulation of Activator Protein-1 and NF-κB in CD8+ T Cells Exposed To Peripheral Self-Antigens

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

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