Facilitation of β Selection and Modification of Positive Selection in the Thymus of Pd-1–Deficient Mice

PD-1 is an immunoglobulin superfamily member bearing an immunoreceptor tyrosine-based inhibitory motif, and disruption of the PD-1 gene results in the development of lupus-like autoimmune diseases. In this study, we examined effects of the PD-1 deficiency on the thymocyte differentiation at the clonal level using T cell receptor (TCR)-β (Vβ8) and TCR-α/β (H-Y and 2C) transgenic mice. In these TCR transgenic lines, PD-1 expression in the thymus was variably augmented, but as in the normal mice, confined largely to the CD4⁻CD8⁻ thymocytes. The transgenic mice crossed with PD-1^−/− mice in the neutral genetic backgrounds exhibited selective increase in the CD4⁺CD8⁺ (DP) population with little effect on other thymocytes subsets. Similarly, the absence of PD-1 facilitated expansion of DP thymocytes in recombination activating gene (RAG)-2^−/− mice by anti-CD3ε antibody injection. On the other hand, H-Y or 2C transgenic PD-1^−/− mice with the positively selecting background showed significantly reduced efficiency for the generation of CD8⁺ single positive cells bearing the transgenic TCR-α/β in spite of the increased DP population. These results collectively indicate that PD-1 negatively regulates the β selection and modulates the positive selection, and suggest that PD-1 deficiency may lead to the significant alteration of mature T cell repertoire.