Regulatory CD4 + T cells redirected against pathogenic CD8 + T cells protect NOD mice from development of autoimmune diabetes.

Autor: Kakabadse D; Diabetes Research Group, Division of Infection and Immunity, Systems Immunity University Research Institute, Cardiff University School of Medicine, Cardiff University, Cardiff, United Kingdom., Chen D; Diabetes Research Group, Division of Infection and Immunity, Systems Immunity University Research Institute, Cardiff University School of Medicine, Cardiff University, Cardiff, United Kingdom., Fishman S; Laboratory of Immunology, MIGAL, Kiryat Shmona, Israel., Weinstein-Marom H; Laboratory of Immunology, MIGAL, Kiryat Shmona, Israel.; Department of Biotechnology, Tel-Hai College, Kiryat Shmona, Israel., Davies J; Diabetes Research Group, Division of Infection and Immunity, Systems Immunity University Research Institute, Cardiff University School of Medicine, Cardiff University, Cardiff, United Kingdom., Wen L; Section of Endocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States., Gross G; Laboratory of Immunology, MIGAL, Kiryat Shmona, Israel.; Department of Biotechnology, Tel-Hai College, Kiryat Shmona, Israel., Wong FS; Diabetes Research Group, Division of Infection and Immunity, Systems Immunity University Research Institute, Cardiff University School of Medicine, Cardiff University, Cardiff, United Kingdom.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2024 Sep 16; Vol. 15, pp. 1463971. Date of Electronic Publication: 2024 Sep 16 (Print Publication: 2024).
DOI: 10.3389/fimmu.2024.1463971
Abstrakt: Introduction: In this study, we report a novel therapeutic approach redirecting antigen-specific CD4 + T cells recognizing a hybrid insulin peptide (BDC2.5 T cell receptor (TCR) transgenic CD4 + T cells) to attract and suppress islet-specific CD8 + T cells T cells in the non-obese diabetic (NOD) mouse model, and prevent the development of autoimmune diabetes.
Methods: Purified BDC2.5 CD4 + T cells were induced to differentiate into regulatory T cells (Tregs). The Tregs were then electroporated with mRNA encoding chimeric human β 2 microglobulin (hβ 2 m) covalently linked to insulin B chain amino acids 15-23 (designated INS-eTreg) or islet-specific glucose-6-phosphatase related protein (IGRP) peptide 206-214 (designated IGRP-eTreg). Immunoregulatory functions of these engineered regulatory T cells (eTregs) were tested by in vitro assays and in vivo co-transfer experiments with β-cell-antigen-specific CD8 + T cells in NOD.Scid mice or by adoptive transfer into young, pre-diabetic NOD mice.
Results: These eTregs were phenotyped by flow cytometry, and shown to have high expression of FoxP3, as well as other markers of Treg function, including IL-10. They suppressed polyclonal CD4 + T cells and antigen-specific CD8 + T cells (recognizing insulin or IGRP), decreasing proliferation and increasing exhaustion and regulatory markers in vitro . In vivo , eTregs reduced diabetes development in co-transfer experiments with pathogenic antigen-specific CD8 + T cells (INS-CD8 + or IGRP-CD8 + cells) into NOD.Scid mice. Finally, when the eTreg were injected into young NOD mice, they reduced insulitis and prevented spontaneous diabetes in the recipient mice.
Conclusion: Our results suggest a novel therapeutic strategy to protect NOD mice by targeting antigen-specific cytotoxic CD8 + T cells, using redirected antigen-specific CD4 + Treg cells, to suppress autoimmune diabetes. This may suggest an innovative therapy for protection of people at risk of development of type 1 diabetes.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Kakabadse, Chen, Fishman, Weinstein-Marom, Davies, Wen, Gross and Wong.)
Databáze: MEDLINE
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