CD4+ T cells can recognize a processed idiotypic peptide derived from the mouse lambda 2(315) immunoglobulin light chain. The idiotypic peptide is presented on the I-E(d) class II major histocompatibility complex molecule. Mice made transgenic for a lambda 2(315)-specific alpha beta T cell receptor have been demonstrated to be specifically resistant against a tumor challenge with the MOPC315 (alpha,lambda 2(315)) plasmacytoma (Lauritzsen, G. F., Weiss, S., Dembic, Z. and Bogen, B., Proc. Natl. Acad. Sci. USA 1994, 91: 5700). That study, however, did not rule out a role of either anti-Id antibodies or T cells expressing nontransgenic specificities due to expression of endogenous T cell receptor (TcR) alpha chains. Also, the role of different T cell subsets in protection was unclear. To remove these ambiguities, we have now made the transgenic mice homozygous for the scid mutation, known to inhibit both Ig and TcR gene rearrangements. Such transgenic SCID mice lack B cells and antibodies while they still have plenty of CD4+ and CD4-8- cells expressing the transgenic alpha beta T cell receptor. The number of CD8+ T cell is dramatically reduced. Even so, transgenic SCID mice are protected against a challenge with MOPC315 plasmacytoma cells. Therefore, B cells, as well as novel T cell receptor specificities created by rearrangements of endogenous alpha-chain genes, are both dispensable for effective immunosurveillance in our system. Surprisingly, we found that transgenic CD8+ and CD4-8- cells are idiotype-specific and I-E(d) restricted. However, these T cell subsets are not required for resistance because adoptive transfer experiments demonstrated that highly purified transgenic SCID CD4+ cells suffice for tumor protection.

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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.