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Naturally Occurring Low Affinity Peptide/MHC Class I Ligands Can Mediate Negative Selection and T Cell Activation¹

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

The affinity/avidity model for T cell development postulates that ligands with high affinity for the TCR are efficient in negative selection, whereas those with lower affinity/avidity favor positive selection. Using the 2C TCR transgenic model, we evaluated the efficacy of ligands with widely differing affinity for the TCR (3 x 10³ to 2 x 10⁶ M^-1) in mediating thymocyte deletion. The relative affinities of the 2C TCR for the p2Ca/L^d, dEV-8/K^b, p2Ca-A3/L^d, and p2Ca/K^b ligands are approximately 1000:50:10:1, respectively. Here we show, using an in vitro assay, that the deletion of 2C CD4⁺CD8⁺ thymocytes is mediated not only by p2Ca/L^d, but also by the lower affinity ligands dEV-8/K^b, p2Ca-A3/L^d, and p2Ca/K^b, albeit at relatively higher peptide concentrations. Deletion mediated by low affinity ligands required CD8, whereas high affinity ligand-mediated deletion was CD8 independent. The p2Ca/K^b and dEV-8/K^b ligands are naturally occurring in H-2^b mice, and others have shown that p2Ca/K^b can induce the maturation of CD4^-CD8⁺2C-TCR^high thymocytes in fetal thymic organ culture. In this study we showed that in addition to deletion, the p2Ca/K^b and dEV-8/K^b ligands, in the presence of exogenous IL-2, induced mature 2C T cell proliferation, albeit at a lower level than that induced by the high affinity p2Ca/L^d ligand. Thus, the same low affinity ligands that can effect negative selection and, in the case of p2Ca/K^b, the maturation of CD8 single-positive thymocytes can also induce the activation of mature CD8 T cells.

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