HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice.
Document Type
Article
Publication Date
12-15-2023
Original Citation
Racine J,
Misherghi A,
Dwyer J,
Maser RS,
Forte E,
Bedard O,
Sattler S,
Pugliese A,
Landry L,
Elso C,
Nakayama M,
Mannering S,
Rosenthal N,
Serreze DV.
HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice. J Immunol. 2023;211(12):1792-805.
Keywords
JMG, SS1, Humans, Mice, Animals, Mice, Inbred NOD, Diabetes Mellitus, Type 1, Insulin, Mice, Transgenic, Diabetes Mellitus, Experimental, Mice, Knockout, Receptors, Antigen, T-Cell, HLA-DQ Antigens
JAX Source
J Immunol. 2023;211(12):1792-805.
ISSN
1550-6606
PMID
37877672
DOI
https://doi.org/10.4049/jimmunol.2300303
Grant
This work was supported by the Juvenile Diabetes Research Foundation United States of America Fellowship 3-PDF-2017-372-A-N and Diabetes Research Connection Grant DRC 27 P20-0201 JR (to J.J.R.). A.M. was supported by an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health under Grant P20GM103423 (via Maine Institutional Development Award Network of Biomedical Research Excellence). J.R.D. was supported during parts of this work by Diabetes Research Connection Grant DRC 43 P21-0334. This work made use of a previously unpublished mouse model developed by the Type 1 Diabetes Resource (Division of Diabetes, Endocrinology, and Metabolic Diseases Grant 1UC4DK097610-01 to D.V.S.). M.N. was additionally supported by Division of Diabetes, Endocrinology, and Metabolic Diseases Grants R01DK133457 and P30DK116073. C.E. and S.M. were supported by National Health and Medical Research Council Grant NHMRC GNT1123586. D.V.S. was supported by Division of Diabetes, Endocrinology, and Metabolic Diseases Grant DK-95735, NIH Office of the Director Grant U54OD020351, uvenile Diabetes Research Foundation United States of America Grant 2-SRA-2018- 568-S-B (to D.V.S., M.N., and S.M.), and Mark Foundation MFCR ASPIRE Serreze FY22. This work was also partly supported by Cancer Center Support Grant CA34196 and NIH Office of the Director Grant U54OD030187.
Abstract
In an effort to improve HLA-"humanized" mouse models for type 1 diabetes (T1D) therapy development, we previously generated directly in the NOD strain CRISPR/Cas9-mediated deletions of various combinations of murine MHC genes. These new models improved upon previously available platforms by retaining β2-microglobulin functionality in FcRn and nonclassical MHC class I formation. As proof of concept, we generated H2-Db/H2-Kd double knockout NOD mice expressing human HLA-A*0201 or HLA-B*3906 class I variants that both supported autoreactive diabetogenic CD8+ T cell responses. In this follow-up work, we now describe the creation of 10 new NOD-based mouse models expressing various combinations of HLA genes with and without chimeric transgenic human TCRs reactive to proinsulin/insulin. The new TCR-transgenic models develop differing levels of insulitis mediated by HLA-DQ8-restricted insulin-reactive T cells. Additionally, these transgenic T cells can transfer insulitis to newly developed NSG mice lacking classical murine MHC molecules, but expressing HLA-DQ8. These new models can be used to test potential therapeutics for a possible capacity to reduce islet infiltration or change the phenotype of T cells expressing type 1 diabetes patient-derived β cell autoantigen-specific TCRs.