Loss of Zbtb32 in NOD mice does not significantly alter T cell responses.

William D. Coley,M. Jubayer Rahman,Kristin V Tarbell,Yi Liu,Yongge Zhao,Charles J. Benck,Chie Hotta-Iwamura

doi:10.12688/f1000research.13864.2

Abstract

Background: We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen targeted to DCIR2 + dendritic cells (DCs) in vivo inhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2 + DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production. Methods: To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis. Results: Although NOD.Zbtb32 -/- male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly, in vitro stimulation of lymphocytes from NOD.Zbtb32 -/- mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes. Conclusions: The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype.

Highlights

Some autoimmune diseases can be managed by the use of immunosuppressive drugs, current treatment options for individuals with Type 1 diabetes (T1D) are largely limited to controlling the disease symptoms instead of addressing the underlying autoimmune assault[1]
We demonstrated that selfantigen presentation by DCIR2+ dendritic cell (DC) but not DEC205+ DCs could promote self-tolerance via increased apoptosis and decreased effector functions in islet-specific CD4 T cells[6]
We previously focused on Zbtb[32] as a potential regulator of T cell tolerance in the Non-Obese Diabetic (NOD) mouse model, and found that this transcription regulator was preferentially induced in autoreactive CD4+ T cells after interacting with tolerogenic DCIR2+ DCs, and that overexpression in T cells inhibited both diabetes and effector T cell expansion[6]

Summary

Introduction

Some autoimmune diseases can be managed by the use of immunosuppressive drugs, current treatment options for individuals with Type 1 diabetes (T1D) are largely limited to controlling the disease symptoms instead of addressing the underlying autoimmune assault[1]. This allowed identification of DC subsets able to induce tolerance against β-islet antigens within the context of chronic autoimmunity found in NOD mice. Using this approach, we demonstrated that selfantigen presentation by DCIR2+ DCs but not DEC205+ DCs could promote self-tolerance via increased apoptosis and decreased effector functions in islet-specific CD4 T cells[6]. Transient overexpression of Zbtb[32] in islet-specific CD4 T cells delayed diabetes development, and decreased both proliferation and IFNγ production in isletspecific CD4+ T cells[6] Together these studies suggest T cell expression of Zbtb[32] plays a role in tolerance induction in NOD mice, and could be a target for treatment

Methods

Results

Conclusion