Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice.
Document Type
Article
Publication Date
3-2015
JAX Source
Clin Exp Immunol 2015 Mar; 179(3):398-413.
Volume
179
Issue
3
First Page
398
Last Page
413
ISSN
1365-2249
PMID
25302633
Grant
AI046629, DK089572
Abstract
Several β cell antigens recognized by T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D) 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 IL2rγ(null) 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 T1D and other T cell-mediated autoimmune diseases. Clin Exp Immunol 2015 Mar; 179(3):398-413.
Recommended Citation
Babad J,
Mukherjee G,
Follenzi A,
Ali R,
Roep B,
Shultz LD,
Santamaria P,
Yang O,
Goldstein H,
Greiner D,
DiLorenzo T.
Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice. Clin Exp Immunol 2015 Mar; 179(3):398-413.