Anti-TIM-4 Monoclonal Antibody Treatment Reduces Autoreactive CD8+ T Cells and Restores Euglycemia in New-Onset Diabetic NOD Mice
- 1Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
- 2Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
Abstract
Type 1 diabetes (T1D) is driven by immune-mediated destruction and dysfunction of pancreatic β-cells, with autoreactive CD8+ T cells serving as important effectors of β-cell injury. T-cell immunoglobulin and mucin domain-containing protein 4 (TIM-4) is expressed predominantly by macrophages and subsets of antigen-presenting cells and participates in phosphatidylserine recognition, efferocytosis, and regulation of adaptive immune responses. We investigated whether short-course TIM-4 targeting alters diabetogenic antigen-specific CD8+ T-cell responses in female non-obese diabetic (NOD) mice with new-onset diabetes. Mice received an anti-TIM-4 monoclonal antibody (3 mg/kg, intraperitoneally, every 2 days for 4 doses). Autoreactive CD8+ T cells were quantified using H-2Kd tetramers loaded with an insulin peptide or the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206–214 peptide, and pancreatic histology and intracellular interferon-γ (IFN-γ), interleukin-17 (IL-17), and forkhead box P3 (FoxP3) staining were assessed. Euglycemia was restored in 8 of 11 treated mice (72.7%) despite cessation of therapy. Anti-TIM-4 monoclonal antibody treatment markedly reduced IGRP206–214-reactive CD8+ T-cell frequencies in pancreatic lymph nodes and pancreas compared with untreated diabetic mice and was associated with preservation of pancreatic islet architecture. Treatment was also associated with lower IFN-γ and IL-17 expression and a higher frequency of FoxP3+ CD4+ T cells in pancreatic lymph nodes. These findings identify TIM-4-associated immune pathways as potential modulators of diabetogenic antigen-specific CD8+ T-cell responses and support further mechanistic evaluation of TIM-4 targeting in autoimmune diabetes.
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BibTeX
@article{kim2026antitim4,
title = {{Anti-TIM-4 Monoclonal Antibody Treatment Reduces Autoreactive CD8+ T Cells and Restores Euglycemia in New-Onset Diabetic NOD Mice}},
author = {Yoon-Ju Kim and You Hyun Jeon and Se-Hyun Oh and Yu-Kyung Chung and Hee-Yeon Jung and Ji-Young Choi and Jang-Hee Cho and Sun-Hee Park and Chan-Duck Kim},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101498},
url = {https://www.mdpi.com/2218-273X/16/10/1498},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Anti-TIM-4 Monoclonal Antibody Treatment Reduces Autoreactive CD8+ T Cells and Restores Euglycemia in New-Onset Diabetic NOD Mice
AU - Yoon-Ju Kim
AU - You Hyun Jeon
AU - Se-Hyun Oh
AU - Yu-Kyung Chung
AU - Hee-Yeon Jung
AU - Ji-Young Choi
AU - Jang-Hee Cho
AU - Sun-Hee Park
AU - Chan-Duck Kim
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101498
UR - https://www.mdpi.com/2218-273X/16/10/1498
AB - Type 1 diabetes (T1D) is driven by immune-mediated destruction and dysfunction of pancreatic β-cells, with autoreactive CD8+ T cells serving as important effectors of β-cell injury. T-cell immunoglobulin and mucin domain-containing protein 4 (TIM-4) is expressed predominantly by macrophages and subsets of antigen-presenting cells and participates in phosphatidylserine recognition, efferocytosis, and regulation of adaptive immune responses. We investigated whether short-course TIM-4 targeting alters diabetogenic antigen-specific CD8+ T-cell responses in female non-obese diabetic (NOD) mice with new-onset diabetes. Mice received an anti-TIM-4 monoclonal antibody (3 mg/kg, intraperitoneally, every 2 days for 4 doses). Autoreactive CD8+ T cells were quantified using H-2Kd tetramers loaded with an insulin peptide or the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206–214 peptide, and pancreatic histology and intracellular interferon-γ (IFN-γ), interleukin-17 (IL-17), and forkhead box P3 (FoxP3) staining were assessed. Euglycemia was restored in 8 of 11 treated mice (72.7%) despite cessation of therapy. Anti-TIM-4 monoclonal antibody treatment markedly reduced IGRP206–214-reactive CD8+ T-cell frequencies in pancreatic lymph nodes and pancreas compared with untreated diabetic mice and was associated with preservation of pancreatic islet architecture. Treatment was also associated with lower IFN-γ and IL-17 expression and a higher frequency of FoxP3+ CD4+ T cells in pancreatic lymph nodes. These findings identify TIM-4-associated immune pathways as potential modulators of diabetogenic antigen-specific CD8+ T-cell responses and support further mechanistic evaluation of TIM-4 targeting in autoimmune diabetes.
SN - 2218-273X
ER -