Fishman, Sigal, Lewis, Mark D., Siew, L. Khai, De Leenheer, Evy, Kakabadse, Dimitri, Davies, Joanne, Ziv, Doron, Margalit, Alon, Karin, Nathan, Gross, Gideon and Wong, F. Susan  ORCID: https://orcid.org/0000-0002-2812-8845
2017.
Adoptive transfer of mRNA-Transfected T cells redirected against diabetogenic CD8 T cells can prevent diabetes.
Molecular Therapy
25
(2)
, pp. 456-464.
10.1016/j.ymthe.2016.12.007
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Abstract
Chimeric major histocompatibility complex (MHC) molecules supplemented with T cell receptor (TCR) signaling motifs function as activation receptors and can redirect gene-modified T cells against pathogenic CD8 T cells. We have shown that β2 microglobulin (β2m) operates as a universal signaling component of MHC-I molecules when fused with the CD3-ζ chain. Linking the H-2Kd-binding insulin B chain peptide insulin B chain, amino acids 15–23 (InsB15–23) to the N terminus of β2m/CD3-ζ, redirected polyclonal CD8 T cells against pathogenic CD8 T cells in a peptide-specific manner in the non-obese diabetic (NOD) mouse. Here, we describe mRNA electroporation for delivering peptide/β2m/CD3-ζ genes to a reporter T cell line and purified primary mouse CD8 T cells. The peptide/β2m/CD3-ζ products paired with endogenous MHC-I chains and transmitted strong activation signals upon MHC-I cross-linking. The reporter T cell line transfected with InsB15–23/β2m/CD3-ζ mRNA was activated by an InsB15–23-H-2Kd-specific CD8 T cell hybrid only when the transfected T cells expressed H-2Kd. Primary NOD CD8 T cells expressing either InsB15–23/β2m/CD3-ζ or islet-specific glucose-6-phosphatase catalytic subunit-related protein, amino acids 206–214 (IGRP206–214)/β2m/CD3-ζ killed their respective autoreactive CD8 T cell targets in vitro. Furthermore, transfer of primary CD8 T cells transfected with InsB15–23/β2m/CD3-ζ mRNA significantly reduced insulitis and protected NOD mice from diabetes. Our results demonstrate that mRNA encoding chimeric MHC-I receptors can redirect effector CD8 against diabetogenic CD8 T cells, offering a new approach for the treatment of type 1 diabetes.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | Elsevier (Cell Press) |
| ISSN: | 1525-0016 |
| Date of First Compliant Deposit: | 1 November 2018 |
| Date of Acceptance: | 5 December 2016 |
| Last Modified: | 09 May 2023 21:41 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/105594 |
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