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Ligand for allogeneic T-cell recognition and its potential applications

Ligand for allogeneic T-cell recognition and its potential applications. Xiongwen Wu Dept. of Immunology Tongji Medical College, the HUST Wuhan, China. Ligand for T cell recognition - pMHC. Multimerized pMHC is able to bind to TCR with high affinity. pMHC dimer ：

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Ligand for allogeneic T-cell recognition and its potential applications

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  1. Ligand for allogeneic T-cell recognition and its potential applications Xiongwen Wu Dept. of Immunology Tongji Medical College, the HUST Wuhan, China

  2. Ligand for T cell recognition - pMHC

  3. Multimerized pMHC is able to bind to TCR with high affinity • pMHC dimer： • Promote or inhibite antigen-specific allogeneic T cells • pMHC tetramer： Detect antigen-specific T cells 图1. pMHC四聚体结构示意图 图2. pMHC二聚体结构示意图

  4. pMHC dimer：promotion or inhibition of antigen-specific allogeneic T cells 1. Antigen-specific inhibition Soluble pMHC dimer binds to TCR without co-stimulatory signal 2. Antigen-specific promotion Cell membrane-bound pMHC dimer raise allo-restricted peptide-specific T cells

  5. Cumulative effect of T cells specific to each peptide epitope could account for the strength and diversity of the allo-response • Xiufang Weng, Zhihui Liang, Xiaoling Lu, Maohua Zhong, Shengjun Lu, Caie Zhang, Jing Deng, Xiongwen Wu*, Feili Gong.Peptide-specific, allogeneic T cell response in vitro induced by a self-peptide binding to HLA-A2.Sci China Ser C-Life Sci. 2007, 50:203-211 Many studies show that allogeneic T-cell responses like syngeneic T-cell responses, are largely peptide-specific

  6. 1. Antigen-specific inhibition Peptide/HLA-A2 dimer inhibits undesired T-cell response

  7. Soluble pMHC dimer inhibits T-cell allo-response in MLC 图7. 可溶性pMHC二聚体诱导特异性的同种T细胞耐受的示意图

  8. Inhibition effect of Tyr/HLA-A2 dimer on T-cell proliferation in MLC is pMHC-specific a, HLA-A2-ve PBLs b, HLA-A2-ve PBLs & T2/Tyr c, b + Tyr368-376 peptide d, b + HIV/HLA-A2 dimer e, b + Tyr/HLA-A2 dimer T2/Tyr: T2 pulsed with Tyr

  9. Inhibition effect of Tyr/HLA-A2 dimer on T-cell proliferation in MLC • Tyr/HLA-A2 dimer in 2nM seems to reach the maximum inhibition • thereverse of the inhibition effect of Tyr/HLA-A2 dimer by HLA-A2-specific mAb BB7.2 • Xiufang Weng, Maohua Zhong, Zhihui Liang, Shengjun Lu, Xueling Chen, Janan Li, Juan Hao, Feili Gong, Xiongwen Wu*.Peptide-dependent inhibition of alloreactive T-cell response by soluble divalent HLA-A2/IgG molecule in vitro.Transplantation. 2007, 84(10):1298-306.

  10. CD8lowCD28- T cells: a human CD8 Ts subset with alloantigen specificity induced by soluble HLA-A2 dimer in vitro

  11. The dimer-expanded CD8lowCD28- T cells exhibit suppression on allo-reactive T cells

  12. The CD8lowCD28- T cells exhibit alloantigen-specific suppression which requires cell-cell contact

  13. Elevated membrane-bound TGF-β1 expression is involved in suppression of the CD8lowCD28‑ T cells

  14. The frequency of CD8lowCD28- T cells is positively associated with plasma levels of soluble HLA class I in human peripheral blood

  15. 2. Antigen-specific promotion generation of allo-restricted peptide-specific T cells exploiting T-cell repertoire of MHC mismatched individuals to circumvent tumor or virus tolerance Xiufang Weng, Xiongwen Wu*, Allo-restricted CTLs generated by co-culture of PBLs and autologous monocytes loaded with allogeneic peptide/HLA/IgG1-Fc fusion protein.Journal of Leukocyte Biology, 2009;85(3):574-81. Xueling Chen, Xiongwen Wu*, Raising allo-restricted CTLs by co-culture of murine splenocytes with autologous macrophage bearing the peptide/allo-MHC complex.Human Immunology, 2009; 70(2):79-84 Song Y, Sun W, Weng X, Liang Z, Yu Q, Wang Z, Ouyang L, Chen J, Wu X, Shen G, Wu X. Tumor rejection effects of allo-restricted tumor peptide-specific CD4⁺ T cells on human cervical cancer cell xenograft in nude mice. Cell Transplant. 2012 Apr 20. [Epub ahead of print]

  16. Tumor rejection effects of allo-restricted tumor peptide-specific CD4+ T cells on human cervical cancer cell xenograft in nude mice

  17. Preparation of the HLA-DR15/IgG1-Fc fusion protein and its binding to HLA-DR15-ve monocyte

  18. CD4+ T cell proliferation & CD4+ Th1 cell induction in co-culturing

  19. allo-restricted and peptide-specific properties of the expanded CD4+ T cells

  20. Tumor rejection effects of allo-restricted E7-specific CD4+T cells on human cervical cancer cell xenografts in nude mice

  21. Research Proposal 03-2002 Allo-reactive T cells comprise various peptide specific T cell clones

  22. Summary • Allogeneic T-cell responses, as syngeneic T-cell responses, are largely pMHC-specific • Soluble pMHC dimer can inhibit T-cell response in an antigen-specific manner • Membrane-associated pMHC dimer is able to raise allo-restricted peptide-specific T cells

  23. Our Team

  24. 致 谢 Thanks

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