title: Development of genetically engineered CD4+ and CD8+ T cells expressing TCRs specific for a M. tuberculosis 38-kDa antigen.
abstract: Cell-mediated immunity is critical to the clearance of Mycobacterium tuberculosis due to the primarily intracellular niche of this pathogen. Adoptive transfer of M. tuberculosis-specific effector T cells has been shown to confer immunity to M. tuberculosis-infected recipients resulting in M. tuberculosis clearance. However, it is difficult to generate sufficient numbers of M. tuberculosis antigen-specific T cells in a short time. Recent studies have developed T cell receptor (TCR) gene-modified T cells that allow for the rapid generation of large numbers of antigen-specific T cells. Many TCRs that target various tumor and viral antigens have now been isolated and shown to have functional activity. Nevertheless, TCRs specific for intracellular bacterial antigens (including M. tuberculosis antigens) have yet to be isolated and their functionality confirmed. We isolated M. tuberculosis 38-kDa antigen-specific HLA class I and class II-restricted TCRs and modified the TCR gene C regions by substituting nine amino acids with their murine TCR homologs (minimal murinization). Results showed that both wild-type and minimal murinized TCR genes were successfully cloned into retroviral vectors and transduced into primary CD4(+) and CD8(+) T cells and displayed anti-M. tuberculosis activity. As expected, minimal murinized TCRs displayed higher cell surface expression levels and stronger anti-M. tuberculosis activity than wild-type TCRs. To the best of our knowledge, this is the first report describing TCRs targeting M. tuberculosis antigens and this investigation provides the basis for future TCR gene-based immunotherapies that can be designed for the treatment of immunocompromised M. tuberculosis-infected patients.
authors.affiliation: Institute of Molecular Immunology, School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Zhang
authors.forename: Yong-Ta
authors.initials: YT
authors.lastname: Huang
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Hao
authors.forename: Zhen-Min
authors.initials: ZM
authors.lastname: Jiang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wen
authors.forename: Ming-Qian
authors.initials: MQ
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Li
authors.initials: L
authors.lastname: Ma
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008074:Lipoproteins / Q000276:immunology*; D051379:Mice; D041681:NIH 3T3 Cells; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
chemical_list: C075966:Ag38 antigen, Mycobacterium tuberculosis; D000942:Antigens, Bacterial; D016207:Cytokines; D000939:Epitopes; D008074:Lipoproteins; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta