Origin and selection of peripheral CD4⁻CD8⁻ T cells bearing α/β T cell antigen receptors in autoimmune gld mice

Abstract

We have analyzed the origin and development of unusual CD4-CD8- alpha/beta T cell receptor-positive peripheral T cells produced in large numbers by mice homozygous for the gld mutation (C3H-gld/gld). These mice may be an important model for investigating processes controlling T cell development. Bone marrow transfers demonstrated that the gld defect was intrinsic to bone marrow-derived cells. Clonal deletion of potentially autoreactive cells was observed in peripheral gld CD4-CD8-, CD4+CD8-, and CD4-CD8+ T cells, as well as mature thymocytes. This suggests that gld CD4-CD8- T cells have passed through the thymus in ontogeny and that gld autoimmunity does not result from a general defect in elimination of self-reactive thymocytes. These observations, combined with demethylation of the CD8 gene in the CD4-CD8- population, support prior expression of CD4 and/or CD8 in gld CD4-CD8- T cell ontogeny, perhaps at a CD4+CD8+ stage. Steroid sensitivity of gld thymocytes and CD4-CD8- T cells was normal. Therefore, we found no gross abnormalities in two major mechanisms of inducible cell death in the gld thymus, the clonal deletion process associated with tolerance and the steroid-inducible endogenous endonuclease thought to be involved in apoptosis of unselected thymocytes. The data suggest that if gld CD4-CD8- T cells arise via escape from normal elimination in the thymus, they must do so by a novel defect in thymic selection (perhaps related to aberrant positive signals) and/or are expanded by an extrathymic process which allows clonal deletion to occur.

Characterization of MHC class-I restricted TCRαβ+ CD4− CD8− double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination

“…Our latest studies indicating that the CD8 coreceptor is mainly necessary to support low affinity TCRs [37] further suggests that the T4H2 TCR is functionally active due to its high affinity towards the gp100 antigen. The proof that high affinity TCRs are able to confer specificity and functional activity has also been given by Kuball et al [38]. They could convincingly show that the gene transfer of a high affinity TCR recognizing the tumor suppressor protein p53 can redirect CD4 + T lymphocytes.…”

Self-reactive T cells can escape clonal deletion in T-cell receptor V beta 8.1 transgenic mice.

“…Founder mice were crossed with CBA/Ca (H-2k, MIs-lb) mice, and individual progeny were typed for H-2 and Mls-i loci. For H-2 typing, spleen cells from each animal were stained with the anti-H-2q monoclonal antibody (mAb) 34-1-2 (no cross reactivity with H-2k) ( (25).…”

CD95 ligand mediates T-cell receptor-induced apoptosis of a CD4+ CD8+ double positive thymic lymphoma

“…This is owing to the fact that selection processes seem not be affected in mice carrying a mutation in the CD95/Fas (lpr) and CD95L/FasL (gld) genes (Wadsworth et al, 1990;Sidman et al, 1992;Moulian and Berrih-Aknin, 1998). In contrast, blocking the activity of the CD95 ligand by a CD95-Fc construct resulted in impaired negative selection (Castro et al, 1996).…”