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- Title
Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice.
- Authors
Babad, J.; Mukherjee, G.; Follenzi, A.; Ali, R.; Roep, B. O.; Shultz, L. D.; Santamaria, P.; Yang, O. O.; Goldstein, H.; Greiner, D. L.; DiLorenzo, T. P.
- Abstract
Several β cell antigens recognized by T cells in the non-obese diabetic ( NOD) mouse model of type 1 diabetes ( T1 D) are also T cell targets in the human disease. While numerous antigen-specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen ( HLA)-transgenic mouse model incorporating human β cell-specific T cells might provide a better platform for evaluating antigen-specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet-infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to 'reprogram' primary human CD8 T cells to express three T cell receptors ( TCRs) specific for a peptide derived from the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein ( IGRP265-273) and recognized in the context of the human class I major histocompatibility complex ( MHC) molecule HLA- A2. The TCRs bound peptide/ MHC multimers with a range of avidities, but all bound with at least 10-fold lower avidity than the anti-viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The β cell-specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon ( IFN)-γ in response to antigen and exhibited cytotoxic activity against peptide-pulsed target cells. The cells engrafted in HLA- A2-transgenic NOD- scid IL2rγnull mice and could be detected in the blood, spleen and pancreas up to 5 weeks post-transfer, suggesting the utility of this approach for the evaluation of T cell-modulatory therapies for T1 D and other T cell-mediated autoimmune diseases.
- Subjects
CYTOTOXIC T cells; LENTIVIRUS diseases; IMMUNODEFICIENCY; LEUCOCYTES; TRANSGENIC mice; COMPARATIVE studies
- Publication
Clinical & Experimental Immunology, 2015, Vol 179, Issue 3, p398
- ISSN
0009-9104
- Publication type
Article
- DOI
10.1111/cei.12465