Presentation of Human Neural Stem Cell Antigens Drives Regulatory T Cell Induction.
Publication Year:
2023
PubMed ID:
37083696
Funding Grants:
Public Summary:
In this work, we demonstrated that human neural stem cells (NSCs) induce regulatory T cell (Treg) recruitment into the CNS by expressing self-antigens recognized by the Tregs. Self-antigens are molecules derived from our own tissues that typically do not induce an immune response because such self-responsiveness would cause autoimmunity. However, Tregs are involved in blocking auto-reactive immune cells by the ability of Tregs to recognize these self-antigens. We found that NSCs express myelin and neuronal self-antigens that active specific populations of Tregs and blockade of antigen-specific Treg function prevents the remyelination we and others have observed following transplantation of human NSCs into multiple sclerosis (MS) mouse models. Moreover, we demonstrate that co-culture of NSCs and immune cells leads to the expansion of populations of such Tregs, supporting the hypothesis that it may be possible to develop durable myelin tolerance in demyelination in MS patients through these myelin- and neuronal-antigen specific Tregs.
Scientific Abstract:
Transplantation of human neural stem cells (hNSCs) is a promising regenerative therapy to promote remyelination in patients with multiple sclerosis (MS). Transplantation of hNSCs has been shown to increase the number of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in the spinal cords of murine models of MS, which is correlated with a strong localized remyelination response. However, the mechanisms by which hNSC transplantation leads to an increase in Tregs in the CNS remains unclear. We report that hNSCs drive the conversion of T conventional (Tconv) cells into Tregs in vitro. Conversion of Tconv cells is Ag driven and fails to occur in the absence of TCR stimulation by cognate antigenic self-peptides. Furthermore, CNS Ags are sufficient to drive this conversion in the absence of hNSCs in vitro and in vivo. Importantly, only Ags presented in the thymus during T cell selection drive this Treg response. In this study, we investigate the mechanisms by which hNSC Ags drive the conversion of Tconv cells into Tregs and may provide key insight needed for the development of MS therapies.