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Positive Selection of CTL by TL Antigen Expressed in the Thymus

Kunio Tsujimura^*, Toshitada Takahashi^*, Akimichi Morita^*,, Hitomi Hasegawa-Nishiwaki^*, Shigeru Iwase^*,, and Yuichi Obata^*

From the ^* Laboratory of Immunology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464, Japan; Department of Dermatology, Nagoya City University School of Medicine, Mizuho-ku, Nagoya 467, Japan; and Department of Chemical Hygiene and Nutrition, Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467, Japan

To elucidate the function of the mouse TL antigen in the thymus, we have derived two TL transgenic mouse strains by introducing Tla^a-3 of A strain origin with its own promoter onto a C3H background with no expression of TL in the thymus. These transgenic mouse strains, both of which express high levels of Tla^a-3-TL antigen in their thymus, were analyzed for their T cell function with emphasis on cytotoxic T lymphocyte (CTL) generation. A T cell response against TL was induced in Tg.Tla^a-3-1, Tg.Tla^a-3-2, and control C3H mice by skin grafts from H-2K^b/T3^b transgenic mice, Tg.Con.3-1, expressing T3^b-TL ubiquitously. Spleen cells from mice that had rejected the T3^b-TL positive skin grafts were restimulated in vitro with Tg.Con.3-1 irradiated spleen cells. In mixed lymphocyte cultures (MLC), approximately 20% and 15% of Thy-1⁺ T cells derived from Tg.Tla^a-3-1 and Tg.Tla^a-3-2, respectively, expressed TCR, whereas almost all those from C3H expressed TCRβ. The MLC from Tg.Tla^a-3-2 and C3H demonstrated high CTL activity against TL, while those from Tg.Tla^a-3-1 had little or none. The generation of CTL recognizing TL in Tg.Tla^a-3-2, but not C3H mice, was confirmed by the establishment of CTL clones. A total of 14 CTL clones were established from Tg.Tla^a-3-2, whereas none were obtained from C3H. Of the 14 CTL clones, 8 were CD8⁺ and 6 were CD4^–CD8^– double negative. The CTL activity of all these clones was TL specific and inhibited by anti-TL, but not by anti-H-2 antibodies, demonstrating that they recognize TL directly without antigen presentation by H-2. The CTL activity was blocked by antibodies to TCR and CD3, and also by antibodies to CD8 and CD8β in CD8⁺ clones, showing that the activity was mediated by TCR and coreceptors. The thymic origin of these CTL clones was indicated by the expression of Thy-1 and Ly-1 (CD5), and also CD8β heterodimers in CD8⁺ clones on their surfaces and by the usage of TCR V4 chains in 12 of the 14 clones. Taken together, these results suggest that Tla^a-3-TL antigen expressed in the thymus engages in positive selection of a sizable population of T cells.

We are indebted to Dr. L.J. Old for his continuous encouragement and advice thoughout these studies. We thank Y. Matsudaira, S. Ozeki, and H. Tamaki for their excellent technical assistance. We thank Dr. K. Furukawa, Dr. K. Kuribayashi, Dr. M. Miyasaka, Dr. M. Muto, Dr. E. Nakayama, Dr. S. Sakaguchi, and Dr. H. Yagita for their kind gifts of monoclonal antibodies.

¹Abbreviations used in this paper: B6, C57BL/6; C3H, C3H/He; cAb, conventional antibody; DN, CD4^–CD8^– double negative; Ltk^–, thymidine kinase-negative L cell; MFI, mean fluorescence intensity; PBR, peptide binding region; RT, reverse transcription.

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