Restoring host-microbe homeostasis via selective chemoattraction of Tregs

Abstract

The disruption of host-microbe homeostasis at the site of periodontal disease is considered a key factor for disease initiation and progress. While the downstream mechanisms responsible for the tissue damage per se are relatively well-known (involving various patterns of immune response operating toward periodontal tissue destruction), we are only beginning to understand the complexity of host-microbe interactions in the periodontal environment. Unfortunately, most of the research has been focused on the disruption of host-microbe homeostasis instead of focusing on the factors responsible for maintaining homeostasis. In this context, regulatory T-cells (Tregs) comprise a CD4+FOXp3 +T-cell subset with a unique ability to regulate other leukocyte functions to avoid excessive immune activation and its pathological consequences. Tregs act as critical determinants of host-microbe homeostasis, as well as determinants of a balanced host response after the disruption of host-microbe homeostasis by pathogens. In periodontitis, Tregs play a protective role, with their natural recruitment being responsible for conversion of active into inactive lesions. With controlled-release technology, it is now possible to achieve a selective chemoattraction of Tregs to periodontal tissues, attenuating experimental periodontitis evolution due to the local control of inflammatory immune response and the generation of a pro-reparative environment.

Keywords: bone regeneration; chemokines; drug delivery systems; inflammation; periodontal disease(s)/periodontitis; regulatory T-Lymphocytes.

Figure 1.

Schematic representation of the overall involvement of Tregs in host-microbe homeostasis. In the gut environment, dendritic cells (DCs) sample antigens through epithelial cells (1). In the pro-tolerogenic milieu conferred by the gut lamina propria, the interaction between dendritic cells (DCs) and naïve T-cells results in the preferential (but not exclusive) generation of iTregs (induced regulatory T-cells) (2) instead of classic T-helper effector cells (3), such as Th1, Th17, and Th2 polarized subsets. Still in the gut lamina propria, the recently generated iTregs contribute to local homeostasis by a positive feedback mechanism, since their secretion products contribute to maintain the local environment as a pro-tolerogenic milieu (4). After developing in the gut environment, Tregs can gain access to the circulatory system (5) and are thought to keep recirculating until migrating to lymph nodes (LN) and/or peripheral tissues in response to specific chemotactic signals. In the LNs (6), Tregs shape the interaction between DCs and naïve T-cells (7), allowing for the development of effector Th cells but limiting excessive proliferation to avoid subsequent excessive responses. In the peripheral tissues (8), Tregs also modulate the fate of DC and Th cell interaction (9), similar to its action at LNs, restraining the response to commensals to maintain host-microbe homeostasis (10), but still allowing efficient effector mechanisms to control potentially harmful antigens. Also, the presence of Tregs in a given environment also results in bystander tolerance (11), where Treg responses to a specific antigen can also suppress the responses to a different antigen in the same environment where the specific antigen is present.

Figure 2.

Schematic representation of the CCL22-releasing formulation that restores host-microbe homeostasis via selective chemoattraction of Tregs to control inflammation and promote repair. The injection of a polymeric controlled-release system in gingival tissue results in a highly stable and steady CCL22 gradient (1), effectively recruiting Tregs to the site of injection in mice (2). The influx of Tregs in the periodontal tissues results in a local increase of IL-10 and TGF-β levels (3), associated with a significant decrease in the influx of inflammatory leukocytes and decreased production of pro-inflammatory, Th1- and Th17-type cytokines (4), without compromising antimicrobial protection (5). The influx of Tregs also restores the MMPs/TIMPs and RANKL/OPG ratio at physiological non-catabolic levels (6), as well increases the levels of pro-reparative markers (7), which collectively are supposed to not only limit tissue destruction but also promote repair.