Positive and negative selection of an antigen receptor on T cells in transgenic mice

Abstract

The T-cell repertoire found in the periphery is thought to be shaped by two developmental events in the thymus that involve the antigen receptors of T lymphocytes. First, interactions between T cells and major histocompatibility complex (MHC) molecules select a T-cell repertoire skewed towards recognition of antigens in the context of self-MHC molecules^1–5. In addition, T cells that react strongly to self-MHC molecules are eliminated by a process called self-tolerance^6–10. We have recently described transgenic mice expressing the αβ T-cell receptor from the cytotoxic T lymphocyte 2C (ref. 11). The clone 2C was derived from a BALB.B (H–2^b) anti-BALB/c (H–2^d) mixed lymphocyte culture and is specific for the L^d class I MHC antigen. In transgenic H–2^b mice, a large fraction of T cells in the periphery expressed the 2C T-cell receptor. These T cells were predominantly CD4^-CD8⁺ and were able to specifically lyse target cells bearing L^d. We now report that in the periphery of transgenic mice expressing L^d, functional T cells bearing the 2C T-cell receptor were deleted. This elimination of autoreactive T cells appears to take place at or before the CD4⁺CD8⁺ stage in thymocyte development. In addition, we report that in H–2⁸ mice, a non-autoreactive target haplotype, large numbers of CDS^* T cells bearing the 2C T-cell receptor were not found, providing strong evidence for the positive selection of the 2C T-cell receptor specificity by H–2^b molecules.