Rebalancing Immune Homeostasis to Treat Autoimmune Diseases

Abstract

During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.

Keywords: autoimmune diseases; immune regulation; immunotherapy; nanoparticles.

Figure 1.

The Precursors of Migratory cDCs Differentiate into Tolerogenic or Immunogenic Antigen-Presenting Cells in Lymphoid Tissues in Response to Environmental Cues and Cytokines. The properties of each are shown.

Figure 2.

Tolerogenic Dendritic Cells (DCs) in Steady-State. Regulatory T cells (Tregs) producing IL-10 and TGF-b interact with immature DCs and induce them to become tolerogenic. These DCs express medium amounts of costimulatory CD80 and CD86 that are sufficient to expand Tregs. In clusters of DCs, Tregs, and self-reactive T cells in lymphoid tissues, self-reactive T cells produce the IL-2 required for Treg expansion. IL-2 and TGF-b produced by the DCs can induce naı¨ve CD4+ T cells to become self-antigen-specific Tregs. Tolerogenic DCs produce the IL-10 necessary to induce Tr-1 Tregs and regulatory B cells (Bregs).

Figure 3.

Immunogenic Dendritic Cells (DCs) in Infections. Immature DCs become immunogenic in response to microbial infections, tissue injury, or proinflammatory cytokines. This strong stimulation activates components of the innate immune system which then trigger Toll-like receptors on immature DCs. The result is their differentiation to a mature immunogenic state. Cytokines produced by these DCs facilitate the induction of T effector cell populations that clear the pathogen. Abbreviation: Th1/2/17, type 1/2/17 T helper cells.

Figure 4.

Tolerance Returning Post-Infection. With resolution, most clonally expanded T cells undergo apoptosis to restore the total number of cells to normal baseline. Phagocytosis of these dendritic cells (DCs) by macrophages and immature DCs generates TGF-b – that is important in switching DCs from immunogenic to mature tolerogenic cells. The steady-state is then ideally restored. Abbreviation: Treg, regulatory T cell.

Figure 5.

Failure To Return to Steady-State Can Result in Autoimmunity. For multifactorial reasons, the failure of a homeostatic compensatory response (following e.g., infection) can result in the persistence of potentially pathogenic self-reactive cells triggered by infection, and might initiate autoimmune disease in susceptible individuals. Abbreviations: DE, dendritic cell; Th1/2/17, type 1/2/17 T helper cells; Treg, regulatory T cell.