Deletion of high-avidity T cells by thymic epithelium.

Abstract

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.

Preferential Escape of Subdominant CD8+ T Cells During Negative Selection Results in an Altered Antiviral T Cell Hierarchy

“…There was nearly a 100-fold difference in their ability to produce IFN-␥ after stimulation with subsaturating levels of peptide Ag. This confirms our previous observations noting large differences in the peptide requirements for inducing CTL activity by these low-avidity and high-avidity T cell populations (9,10), which is consistent with the avidity model for thymic negative selection (2). To further assess these differences, we performed functional fingerprinting analysis using altered peptide ligands for stimulation (Fig.…”

“…N egative selection is a unique process that determines which T cells will be deleted in the thymus and which ones will differentiate into mature cells that are then released into the periphery (1)(2)(3)(4)(5). Positive selection occurs first and requires that T cells demonstrate at least a weak interaction with self-peptides presented by the appropriate MHC molecules (6,7).…”

Normal Thymic Architecture and Negative Selection Are Associated with Aire Expression, the Gene Defective in the Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

“…However, ample evidence exists that medullary epithelial cells are capable to delete or anergize self-reactive T cells (52,54,68). Here we have demonstrated that Aire expression 1) correlates with the correct structural organization of the thymic microenvironment, 2) is localized to cells and anatomical sites known to effect negative selection, and 3) is modulated by thymocytes undergoing negative selection.…”

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

“…T cells capable of responding to their antigen in vitro can be tolerant to the same antigen in vivo (33)(34)(35). To address this possibility, G206 mice were immunized with p206 in incomplete Freund's adjuvant (IFA), and ex vivo T cell proliferation assays were performed 5 days later with draining lymph node cells.…”