Generation of β cell‐specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen‐transgenic mice

Summary Several β cell antigens recognized by T cells in the non‐obese diabetic ( NOD ) mouse model of type 1 diabetes ( T 1 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 CD 8 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 ( IGRP 265–273 ) and recognized in the context of the human class I major histocompatibility complex ( MHC ) molecule HLA ‐ A 2. The TCR s 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 CD 8 T cells generated by lentiviral transduction with one of the TCR s released interferon ( IFN)‐ γ in response to antigen and exhibited cytotoxic activity against peptide‐pulsed target cells. The cells engrafted in HLA ‐ A 2‐transgenic NOD ‐ scid IL 2rγ 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 T 1 D and other T cell‐mediated autoimmune diseases.