Constitutively Active Stat5b Expression in Dendritic Cells Enhances Treg-Mediated Elimination of Autoreactive CD8+ T Cells in Autoimmune Diabetes

TL;DR

A mutation in dendritic cells in diabetic mice improves Treg function, reducing harmful CD8+ T cells and preventing diabetes.

Contribution

Constitutively active Stat5b in dendritic cells enhances Treg-mediated elimination of autoreactive CD8+ T cells in autoimmune diabetes.

Findings

NOD.Stat5b-CA mice show expanded Treg populations and reduced CD8+ T cells in peripheral lymphoid organs.

Tregs from NOD.Stat5b-CA mice exhibit increased activation markers and cytotoxic potential.

CD8+ T cell reduction is mediated via Treg cytotoxic activity, including perforin and granzyme B expression.

Abstract

In type 1 diabetes (T1D) in non-obese diabetic (NOD) mice, dendritic cells (DCs) exhibit a Stat5b mutation that impairs regulatory T cell (Tregs) numbers and suppressive function. To correct this defect, we generated transgenic NOD mice expressing constitutively active Stat5b (NOD.Stat5b-CA) in DCs, which conferred protection from diabetes that was associated with an expanded Treg population and a marked reduction in CD8+ T cell frequencies in secondary lymphoid organs. However, the phenotypic characteristics and underlying mechanisms to eliminate CD8+ T cells in NOD.Stat5b-CA mice are unknown. In this study, we found that the frequency of Tregs was significantly higher in the thymus and peripheral lymphoid organs of NOD.Stat5b-CA mice compared with NOD mice. Tregs in the peripheral lymphoid organs exhibited increased expression of activation markers CD69 and OX40, alongside reduced CD62L. We also found that CD8+ T cell frequencies were reduced in the peripheral organs but not in the thymus of NOD.Stat5b-CA mice, while CD4+ T cell frequencies remained unchanged across all organs. Furthermore, NOD.Stat5b-CA mice exhibited a reduced frequency of central Tregs (CD62Lhigh CD44low) and increased frequency of effector Tregs (CD62Llow CD44high) under steady-state conditions compared to NOD mice. Notably, Tregs from NOD.Stat5b-CA mice displayed enhanced cytotoxic activity, evidenced by increased expression of perforin, granzyme B, and Fas ligand, potentially mediating CD8+ T cell frequency reduction. Collectively, these findings highlight a novel role for Stat5b-CA.DC-educated Tregs in modulating immune responses by eliminating peripheral pathogenic CD8+ T cells via cytotoxic pathways, thereby contributing to immune regulation in NOD.Stat5b-CA mice.

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