Nanoparticles for the Induction of Antigen-Specific Tregs

Abstract

Expansion of memory-like CD8+ Tregs with NPs During the course of spontaneous autoimmune Type 1 diabetes in nonobese diabetic (NOD) mice, a population of low-avidity self-reactive CD8 T cells acquires a regulatory phenotype. To expand these CD8 Tregs, Santamaria and coworkers developed NPs containing complexes of disease-relevant self-peptides and the class I MHC (pMHC-NPs)[4]. The administration of pMHC-NPs abrogated the diabetogenic response and restored normoglycemia in diabetic NOD mice, and also in humanized NOD mice [4]. Mechanistic studies determined that pMHC-NPs were not taken up by CD11b, CD11c or B cells, and instead targeted T cells in vivo, leading to the expansion of regulatory memory-like CCR7 CXCR3CD62LCD44CD122CD8 T cells, a phenotype that differs from that of ‘classical’ memory T cells. The CD8 Tregs induced by pMHC-NPs produced IFN-g, but did not proliferate or secrete IL-2 in response to stimulation. Moreover, these CD8 Tregs showed suppressive activity in vitro and in vivo, as a result of their ability to kill APCs through a mechanism that involved IFN-g, indoleamine 2,3-dioxygenase (IDO) and perforin. An important feature of the suppressive activity of the CD8 Tregs induced by pMHC-NPs is that they suppressed the activation of T cells of different antigen specificities. Since several self-antigens are usually targeted during the course of autoimmune diseases [5] and the identity of all the antigens targeted by the autoimmune response in each individual patient is usually unknown, this bystander suppression Specialized populations of Tregs control activity in healthy individuals. Treg deficits are usually associated with the development of auto immune diseases. Thus, the expansion of antigen-specific Tregs is viewed as a potential therapeutic approach for autoimmune disorders; however, methods for generating significant numbers of antigenspecific Tregs in vivo or in vitro are still missing. Nanotechnology offers new tools for the expansion of antigen-specific Tregs and the treatment of autoimmune disorders. This article discusses recent examples of the use of nano technologybased approaches to re-establish immune tolerance and treat autoimmune diseases. Autoimmune diseases result from the dysregulated reactivity of the immune system against self-antigens. In healthy individuals, the activity of the immune system is controlled by specialized populations of Tregs [1]. In patients afflicted by autoimmune diseases, however, Treg deficits are usually found [2]. Thus, the generation of antigen-specific Tregs is viewed as a promising approach for the treatment of autoimmune disorders, but methods for generating significant numbers of antigen-specific Tregs in vivo or in vitro are still missing. Nanoparticles (NPs) have unique physical and chemical features that prompted their use in medicine. Some of these features are of particular interest for the field of drug delivery [3]: