Functional clonal deletion of cytotoxic T-lymphocyte precursors in chimeric thymus produced in vitro from embryonic Anlagen.

Good, Michael F.; Pyke, Kenneth W.; Nossal, G. J. V.

doi:10.1073/pnas.80.10.3045

Cited by 39 publications

(12 citation statements)

References 27 publications

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“…In other models, using either TCR transgenic mice or deletion by superantigens of T cells bearing certain TCR Vp chains, partial deletion of reactive T cells by TE has been described in some models (4,(19)(20)(21)(22), whereas others saw no effects (17,26). Interestingly, Schonrich et al (17), using the same Kb-specific Des-TCR transgenic mice that we used in the present study, reported that expression of Kb on medullary TE did not induce deletion of Des-TCR+CD8+ T cells in the thymus.…”

Section: Resultsmentioning

confidence: 99%

Deletion of high-avidity T cells by thymic epithelium.

Hoffmann

Heath

Ruschmeyer

et al. 1995

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

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Tolerance induction by thymic epithelium induces a state of so-called "split tolerance," characterized in vivo by tolerance and in vitro by reactivity to a given thymically expressed antigen. Using a model major histocompatibility complex class I antigen, H-2Kb (Kb), three mechanisms of thymic epithelium-induced tolerance were tested: induction of tolerance of tissue-specific antigens exclusively, selective inactivation of T helper cell-independent cytotoxic T lymphocytes, and deletion of high-avidity T cells. To this end, thymic anlagen from Kb-transgenic embryonic day 10 mouse embryos, taken before colonization by cells of hemopoietic origin, were grafted to nude mice. Tolerance by thymic epithelium was not tissue-specific, since Kb-bearing skin and spleen grafts were maintained indefinitely. Only strong priming in vivo could partially overcome the tolerant state and induce rejection of some skin grafts overexpressing transgenic Kb. Furthermore, the hypothesis that thymic epithelium selectively inactivates those T cells that reject skin grafts in a T helperindependent fashion could not be supported. Thus, when T-cell help was provided by a second skin graft bearing an additional major histocompatibility complex class II disparity, tolerance to the Kb skin graft was not broken. Finally, direct evidence could be obtained for the avidity model of thymic epithelium-induced negative selection, using Kbspecific T-cell receptor (TCR) transgenic mice. Thymic epithelium-grafted TCR transgenic mice showed a selective deletion of tkpse CD8+ T cells with the highest density of the clonotyph 'CR. These cells presumably represent the T cells with the $ghest avidity for Kb. We conclude that split tolerance induced by thymic epithelium was mediated by the deletion of those CD8+ T lymphocytes that have the highest avidity for antigen.

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Section: Resultsmentioning

confidence: 99%

Deletion of high-avidity T cells by thymic epithelium.

Hoffmann

Heath

Ruschmeyer

et al. 1995

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

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“…In these studies as well as in the present one, the limiting-dilution curves obtained were linear and applied to zero-order kinetics, which indicates that only one cell type was limiting for the response. This constituted one argument in favor of a mechanism of functional clonal deletion rather than of active suppression (3,18). On the other hand, it cannot be excluded that the frequency of suppressor cells in these cultures is so high that they cannot be isolated from cytotoxic precursor cells by the means of limiting dilution.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic T-cell precursors revealed in neonatally tolerant mice.

Stockinger¹

1984

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

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Induction of neonatal tolerance leads to a profound reduction in cytotoxic T-lymphocyte precursor frequencies against the tolerated alloantigen ("tolerogen") as evaluated by limiting-dilution analysis. The curves obtained were linear within the range tested and, thus, did not yield evidence for any dissociation of cytotoxic precursors from regulatory cell populations. However, it could be shown that cytotoxic T-lymphocyte precursor frequencies against the tolerogen increased drastically if the tolerant spleen cells were adsorbed, prior to limiting-dilution culture, on monolayers of syngeneic blasts expressing receptors for the tolerogen but not if they were adsorbed on syngeneic blasts against third-party antigens. This finding implies that cytotoxic precursor cells against the tolerogen are not clonally deleted in tolerant animals but rather are suppressed by a regulatory cell population that is present at high frequency and presumably acts in an anti-idiotypic fashion.

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“…However, the questions of the site of tolerance induction and the mechanisms involved are uncertain. In a recent report, embryonic thymic epithelial rudiments, removed prior to their population by migrant stem cells, were cultured with fetal liver fragments as a source of stem cells (Good et al, 1983). The thymus cultures, when harvested, were examined in limiting dilution assays for precursors of cytotoxic cells to MHC antigens of the fetal liver donor, thymus epithelium, and third party, respectively.…”

Section: Early Differentiation Of the Thymic Stroma And Its Influencementioning

confidence: 99%

Early events in T lymphocyte genesis in the fetal thymus

Owen

Jenkinson

1984

Am. J. Anat.

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There is considerable uncertainty about the nature and level of maturation of the stem cells which colonize the thymus. Arguments are presented here which raise doubts about the claims that these cells have undergone substantial maturation along the T-lineage pathway prior to migration to the thymus. Instead, emphasis is placed on the role of thymic stromal cells in T-lymphocyte maturation. The heterogeneous nature of these cells is well established, but progress is described in analyzing the various cell types and their embryological origins. In particular, the expression of the major histocompatibility complex (MHC) antigens on thymic stromal cells might be relevant to the understanding of restriction and tolerance. The early phases of thymus lymphocyte differentiation are described; but no clear account of the generation of T-cell subsets from immature cells can, as yet, be offered.

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Functional clonal deletion of cytotoxic T-lymphocyte precursors in chimeric thymus produced in vitro from embryonic Anlagen.

Cited by 39 publications

References 27 publications

Deletion of high-avidity T cells by thymic epithelium.

Deletion of high-avidity T cells by thymic epithelium.

Cytotoxic T-cell precursors revealed in neonatally tolerant mice.

Early events in T lymphocyte genesis in the fetal thymus

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