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Different Development of Myelin Basic Protein Agonist- and Antagonist-Specific Human TCR Transgenic T Cells in the Thymus and Periphery¹

Kazuyuki Kawamura^2,*, Karen Yao^2,*, Jacqueline A. Shukaliak-Quandt^*, Jaebong Huh^*, Mirza Baig^*, Laura Quigley^*, Naoko Ito, Antje Necker, Henry F. McFarland^*, Paolo A. Muraro^*,, Roland Martin^*,¶ and Kouichi Ito^3,*,

^* Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892; Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854; Antibody Department, Beckman Coulter, Marseilles, France; Department of Cellular and Molecular Neuroscience, Imperial College London, London, United Kingdom; and ^¶ Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, University Medical Center Eppendorf, Hamburg, Germany

Myelin basic protein (MBP)-specific T cells are thought to play a role in the development of multiple sclerosis. MBP residues 111–129 compose an immunodominant epitope cluster restricted by HLA-DRB1*0401. The sequence of residues 111–129 of MBP (MBP_111–129) differs in humans (MBP122:Arg) and mice (MBP122:Lys) at aa 122. We previously found that 50% of human MBP_111–129 (MBP122:Arg)-specific T cell clones, including MS2-3C8 can proliferate in response to mouse MBP_111–129 (MBP122:Lys). However, the other half of T cell clones, including HD4-1C2, cannot proliferate in response to MBP_111–129 (MBP122:Lys). We found that MBP_111–129 (MBP122:Lys) is an antagonist for HD4-1C2 TCR, therefore, MS2-3C8 and HD4-1C2 TCRs are agonist- and antagonist-specific TCRs in mice, respectively. Therefore, we examined the development of HD4-1C2 TCR and MS2-3C8 TCR transgenic (Tg) T cells in the thymus and periphery. We found that dual TCR expression exclusively facilitates the development of MBP_111–129 TCR Tg T cells in the periphery of HD4-1C2 TCR/HLA-DRB1*0401 Tg mice although it is not required for their development in the thymus. We also found that MS2-3C8 TCR Tg CD8⁺ T cells develop along with MS2-3C8 TCR Tg CD4⁺ T cells, and that dual TCR expression was crucial for the development of MS2-3C8 TCR Tg CD4⁺ and CD8⁺ T cells in the thymus and periphery, respectively. These results suggest that thymic and peripheral development of MBP-specific T cells are different; however, dual TCR expression can facilitate their development.

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¹ This work was supported by the National Multiple Sclerosis Society (K.K.) and by the Canadian Multiple Sclerosis Society (J.A.S.-Q.).

² K.K. and K.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Kouichi Ito, Department of Neurology, Robert Wood Johnson Medical School, Research Building Room 182, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, NJ 08854. E-mail address: itoko{at}umdnj.edu

⁴ Abbreviations used in this paper: MS, multiple sclerosis; MBP, myelin basic protein; TCC, T cell clone; Tg, transgenic; KO, knockout; DP, double positive; HA, hemagglutinin.