B7-H4.Ig inhibits the development of Type 1 diabetes by regulating Th17 cells in NOD mice

I. Fang Lee, Xiaojie Wang, Jianqiang Hao, Noushin Akhoundsadegh, Lieping Chen, Linda Liu, Sol Langermann, Dawei Ou, Garth L. Warnock

Research output: Contribution to journalArticle

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by immunological destruction of insulin-producing pancreatic β-cells and subsequent hyperglycemia. The non-obese diabetic (NOD) mouse strain spontaneously develops a disease similar to human T1D and is commonly used as an animal model for studying this disease. We have previously shown that the administration of B7-H4-immunoglobulin fusion protein (B7-H4.Ig), a newly identified T-cell co-inhibitory signaling molecule, blocks the onset of diabetes in NOD mice. However, the mechanism(s) by which B7-H4 protects NOD mice from T1D is not fully understood. IL-17 is a pro-inflammatory cytokine, produced by Th17 cells, that activates T cells and other immune cells to produce a variety of cytokines and chemokines. Increasing evidence has shown that therapeutic agents targeting the IL-17 molecule or directly inhibiting IL-17-producing cells regulate autoimmune diabetes in NOD mice, suggesting that IL-17 is involved in the pathogenesis of this disease. In this study, we investigate whether B7-H4.Ig treatment inhibits the generation of Th17 cells which subsequently decreases IL-17 production and prevents the onset of T1D in NOD mice. Pre-diabetic female NOD mice were injected intraperitoneally with control mouse IgG or B7-H4.Ig starting at 4. weeks of age for 12. weeks. Our data showed that the frequency of Th17 cells in B7-H4.Ig-treated mice was significantly decreased. In addition, our data showed that B7-H4.Ig-treated mice had decreased levels of pro-inflammatory cytokines and Th17-associated cytokines, and an increased level of the potent Th17 inhibitor IFN-γ. To further investigate the effect of B7-H4.Ig on differentiation of Th17 cells, we co-cultured splenocytes with Th17-polarizing cytokines in the absence or presence of B7-H4.Ig. Our results indicated that splenocytes, under the Th17 driving conditions in the presence of B7-H4.Ig, had significantly decreased the numbers of Th17 cells compared to cells co-cultured in the absence of B7-H4.Ig. Together, this study suggests that blocking the generation of Th17 cells with the administration of B7-H4.Ig effectively inhibits the development of T1D in NOD mice.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalCellular Immunology
Volume282
Issue number1
DOIs
StatePublished - Mar 2013
Externally publishedYes

Fingerprint

Th17 Cells
Inbred NOD Mouse
Type 1 Diabetes Mellitus
Interleukin-17
Cytokines
T-Lymphocytes
Animal Disease Models
Chemokines
Hyperglycemia
Autoimmune Diseases
Immunoglobulins
Cultured Cells
Immunoglobulin G
Insulin

Keywords

  • B7-H4
  • Cell differentiation
  • Interferon-gamma
  • T helper 17 Cells
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology

Cite this

Lee, I. F., Wang, X., Hao, J., Akhoundsadegh, N., Chen, L., Liu, L., ... Warnock, G. L. (2013). B7-H4.Ig inhibits the development of Type 1 diabetes by regulating Th17 cells in NOD mice. Cellular Immunology, 282(1), 1-8. https://doi.org/10.1016/j.cellimm.2013.03.005

B7-H4.Ig inhibits the development of Type 1 diabetes by regulating Th17 cells in NOD mice. / Lee, I. Fang; Wang, Xiaojie; Hao, Jianqiang; Akhoundsadegh, Noushin; Chen, Lieping; Liu, Linda; Langermann, Sol; Ou, Dawei; Warnock, Garth L.

In: Cellular Immunology, Vol. 282, No. 1, 03.2013, p. 1-8.

Research output: Contribution to journalArticle

Lee, IF, Wang, X, Hao, J, Akhoundsadegh, N, Chen, L, Liu, L, Langermann, S, Ou, D & Warnock, GL 2013, 'B7-H4.Ig inhibits the development of Type 1 diabetes by regulating Th17 cells in NOD mice', Cellular Immunology, vol. 282, no. 1, pp. 1-8. https://doi.org/10.1016/j.cellimm.2013.03.005
Lee, I. Fang ; Wang, Xiaojie ; Hao, Jianqiang ; Akhoundsadegh, Noushin ; Chen, Lieping ; Liu, Linda ; Langermann, Sol ; Ou, Dawei ; Warnock, Garth L. / B7-H4.Ig inhibits the development of Type 1 diabetes by regulating Th17 cells in NOD mice. In: Cellular Immunology. 2013 ; Vol. 282, No. 1. pp. 1-8.
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