Autoreactive CD4+ T Cells Protect from Autoimmune Diabetes via Bystander Suppression Using the IL-4/Stat6 Pathway

Abstract

Targeted immune regulation can be achieved by use of tissue-specific T cells and offers the potential for organ-specific suppression of destructive autoimmune processes. Here, we report the generation and characterization of insulin B chain-specific "autoreactive" CD4+ regulatory T cells that locally suppress diabetogenic T cell responses against an unrelated self-antigen (viral transgene) in a virus-induced model for type 1 diabetes. Interleukin 4 (IL-4) is essential for prevention of diabetes since regulatory T cells cannot be induced in the absence of IL-4 or stat6 (IL-4 signaling pathway). Our observations demonstrate that autoreactive regulatory T cells can suppress autoreactive destructive T cell activity of differential antigenic specificity locally in the pancreatic draining lymph node, probably via cytokine-mediated modulation of antigen-presenting cells.

CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

“…It is consistent with reports from murine models of autoimmunity, such as experimental autoimmune encephalomyelitis and diabetes, where disease pathology was associated with signaling via STAT4, while the STAT6 signaling pathway was associated with resistance to disease pathology [22,23]. This paradigm was previously interpreted as a reflection of the opposing functions of Th1 (STAT4-dependent) and Th2 (STAT6-dependent) effector cells, where pathogenic Th1 cells were believed to be counter-regulated by Th2 cells [22].…”

Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6

“…STAT6 deficiency did not influence development of autoimmune diabetes in a streptozotocin model of diabetes, (40) and did not increase severity of colitis in TCR␣ Ϫ/Ϫ mice (41). At the same time, IL-4 has been reported to be necessary for the induction of regulatory cells that prevent diabetes (42) and STAT4 Ϫ/Ϫ NOD mice were resistant to induction of diabetes and experimental allergic encephalomyelitis (43,44). STAT6 Ϫ/Ϫ mice were more susceptible to myasthenia gravis (45).…”

Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice

“…Immune responses to both GAD65 and insulin can be found in human type I diabetes (54). Furthermore, tolerance induction to GAD65 (55)(56)(57)(58) and insulin (57,(59)(60)(61) in prediabetic animals can mitigate and, in some cases, prevent diabetes.…”