Preferential positive selection of T lymphocytes which express two different TCR alpha chains, an endogenous and a...

A hallmark of positive selection in T-cell receptor (TCR)-transgenic mice is a strong skewing towards the CD4+ or the CD8+ subset, depending on the class II or I restriction of the TCR, respectively. However, previous experiments in TCR transgenic mice specific for an Ig light chain (lambda 2(315)/I-Ed class II molecule did not fit into this scheme because the authors observed an anomalous skewing towards CD8. In this paper the authors show that endogenous TCR alpha chains are expressed on > 90% of CD4+ and CD8+ cells in this particular transgenic strain, even on a selecting H-2d haplotype. Endogenous TCR alpha chains are first detected when double-positive thymocytes down-regulate either CD4 or CD8. Endogenous V alpha seems to influence generation of T-cell subsets because CD4+ and CD8+ cells express different frequencies of endogenous V alpha 2 and V alpha 8. In the absence of endogenous TCR alpha chains in recombination-deficient TCR-transgenic severe combined immunodeficiency (SCID) mice, a strong skewing towards CD4+ T cells is seen, but such mice are severely T-cell deficient. As an explanation for these results, the authors suggest that the transgenic TCR has a too low affinity for efficient positive selection, therefore, TCR alpha gene rearrangements proceed. Endogenous TCR alpha paired with transgenic TCR beta could bind to class I or class II molecules, enhance positive selection and thereby production of CD4+ or CD8+ cells. Most of the 'mismatched' CD8+ cells are lambda 2(315)-specific and I-Ed class II restricted, and may function as idiotype-specific suppressors of B cells. These results may help explain the origin of dual TCR alpha T cells. Furthermore, the authors suggest that T cells 'mismatched' for co-receptor/TCR MHC-specificity may be enriched among dual TCR alpha T cells.