Regulatory T cell-based therapies for autoimmunity

Abstract

Autoimmune disorders are long-term diseases that adversely affect the quality of life for patients, and they are one of the top ten leading causes of death. While each autoimmune disorder is unique, they all are caused by a breakdown of tolerance against endogenous proteins. This leads to auto-inflammatory events that promote the destruction of organs in a humoral and cellular immune mediated manner. Treatment options for autoimmunity can involve the use of chemical and biologic agents that suppress inflammation. While these treatment options for patients have shown to be beneficial in autoimmunity, they can result in patients being vulnerable to opportunistic infections. Newer therapies aim to identify methods to specifically block auto-inflammatory immune cells while allowing for an intact immune response to other antigens. T regulatory (Treg) cells are a subtype of the adoptive immune cell that is capable of suppressing inflammatory events in an antigen-specific manner, but they are often poorly functioning within autoimmune patients. Treg cells have been well characterized for their immune modulating capabilities and preclinical and early clinical studies support their therapeutic potential for antigen-specific immune suppression. This review will examine the current understanding of Treg cell function and the therapeutic potential of enhancing Treg cells in patients with inflammatory disorders.

Figure 1

Treg cell mechanism of suppression in autoimmunity. (A) When activated, Treg cells are capable of driving the formation of tolerogenic APCs via the secretion of regulatory cytokines (e.g., TGF-β and IL-10). Tolerogenic APCs activate antigen-specific CD4+ T cells and skew them towards a regulatory phenotype. (B) IL-2 cytokine depletion drives the upregulation of PD-1 on activated CD8+ T cells. Upregulation of PD-L1 by tolerogenic APCs, leave CD8 T cells vulnerable to cell death in a PD-1/PDL-1 dependent manner. (C) B cells are capable of presenting antigens to Treg cells. Once activated by B cells, Tregs suppress the secretion of autoantibodies via direct killing of autoinflammatory B cells in a perforin and granzyme dependent manner.