Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules.

Abstract

The vast majority of mature T cells are either of the CD4+ 8-or the CD4-8+ phenotype. The CD4 cell surface glycoprotein is expressed primarily on the surface of helper T cells, whose TCR recognize antigen on APCs in the context of class II MHC molecules. The CD8 molecule is primarily expressed on T cells, in particular CTL, whose TCR recognize antigen in the context of class I MHC molecules.The TCR on helper T cells and CTL has been identified as a disulfide-linked ado heterodimer with a molecular weight of 80,000-90,000 (reviewed in reference 1). The binding of CD4 and CD8 molecules to nonpolymorphic regions of class II and class I MHC molecules, respectively, enhances the binding of the TCR to its ligand and may also contribute to signals leading to T cell activation (2, 3).We have constructed TCR transgenic mice with the aim to study the selection ofthe T cell repertoire. To this end, u and a transgenes obtained from an HYspecific, H-21)6-restricted cytolytic CD4-8 + T cell clone were injected into fertilized eggs . We have reported that in female ca/(3 transgenic mice a large proportion of T cells is male specific and expresses both ce and (3 transgenes . In male mice we found that cells with an abnormal CD4/CD8 phenotype accumulated in the periphery, with the vast majority of a//3 T cells being CD4 -8 -and a minority being CD4-8+ . The latter expressed, however, low levels of CD8 accessory molecules. Due to the lack of an appropriate antibody we could not directly address the question as to whether or not these cells expressed the transgenic receptor. Here we describe the use ofmAbs that detect cells expressing both a and a transgenes . Using these antibodies we find that in male H-2D b mice the vast majority of peripheral T cells express both a and a transgenes . Our studies indicate that despite the fact that precursor T cells, which express a low density of the transgenic TCR, are largely deleted in the thymus of male transgenic mice (4), the majority of T cells spared by the deletion express a high density of the transgenic TCR but a low density of CD8 molecules.

Role of TCR‐restricting MHC density and thymic environment on selection and survival of cells expressing low‐affinity T cell receptors

“…Briefly, in H-Y-specific TCR transgenic females, absence of the peptide H-Y and presence of TCR-restricting H-2D b resulted in positive selection and further survival in the periphery of H-Yspecific CD8 § g hi transgenic TCR § g + cells (Fig. 1A) [16,19]. However, only up to 40% of peripheral CD8 § g + cells expressed the H-Y-specific transgenic TCR ( Fig.…”

“…However, cells showing a down-regulation of their coreceptor and transgenic TCR, resulting in CD8 § g lo transgenic TCR § g + cells, were present in TCR transgenic males (Fig. 1B) [16,19,23]. CD8 § g lo transgenic TCR § g + cells, where binding to self-peptide/MHC complex is most likely to be of low avidity, apparently escaped negative selection in the thymus.…”

“…CD8 § g lo transgenic TCR § g + cells, where binding to self-peptide/MHC complex is most likely to be of low avidity, apparently escaped negative selection in the thymus. These cells, which migrate into the periphery as mature self-MHC-restricted, H-Ynon-reactive T cells, do not proliferate after contact with male stimulator cells but react against non-H-Y antigens [16,19]. H-Y-specific TCR transgenic mice, which do not express TCR-restricting MHC class I H-2D b molecules, did not show positive selection of H-Y-specific CD8 § g hi transgenic TCR § g + cells (Fig.…”

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

“…Negative selection of thymocytes was tested using the MHC class I-restricted H-Y TCR-transgenic system to induce negative selection of thymocytes specific for the male H-Y Ag presented in male mice (18), but no impairment was observed in aPix 2 mice (Fig. 4C).…”

Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

“…3 Interestingly, there is a population of CD8 ϩ T cells, which express a low level of CD8 (referred to as CD8 lo ), that are resistant to deletion in male mice. 4,5 The CD8 lo cells are selfreactive, as they expand after transfer into male but not female H-2 b nude mice. 5 These cells express high levels of CD44 5 and interleukin-2 receptor ␤ (IL-2R␤; CD122) 6 that are characteristic of memory T cells.…”