The role of regulatory T cells in the regulation of upper airway inflammation

Abstract

Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) are inflammatory diseases of the upper airway, with a similar immunologic profile, characterized by aberrant and persistent type 2 inflammation. One cell population that has been identified as altered in both disease types is regulatory T cell (Treg). Tregs have the capacity to modulate T-effector function and suppress inflammatory cytokine production in a broad range of cell types. Given the ability of Tregs to control inflammation, the role of Tregs in respiratory diseases has attracted much attention. As discussed in this article, alterations in the Treg numbers and function, or both, have been identified in AR and CRSwNP, although much of the data is conflicting. Here, we explored what is known and, in many cases, unknown about the mechanisms by which Tregs differentiate and function, and how these functions can be controlled in the mucosal microenvironment. By gaining a greater understanding of these processes, it may be possible to harness the natural immunosuppressive activity of Tregs to ameliorate the chronic inflammation associated with AR and CRSwNP.

Figure 1.

The influence of airway-derived factors in regulatory T cell (Treg) migration and differentiation. (A) The presence of Tregs in the airway can be influenced by a number of locally produced mediators. Airway epithelial cells can produce factors such as 1,25-dihydroxyvitamin D3 (1,25[OH]D₃) and transforming growth factor (TGF) β both of which can induce the differentiation of naive T cells to become Tregs. Epithelial cells also produce chemotactic factors, such as chemokine (C-C motif) ligand (CCL) 1 and CCL17, which induce Treg migration through C-C Chemokine Receptor (CCR) 4 and CCR8 receptors signaling. Mediators made by local immune infiltrates, such as macrophage production of CCL22, and T-helper (Th) type 1 cell production of interleukin (IL) 16 can also induce Treg migration to the airway. (B) Airway-produced factors can also impair Treg functions. Th2 and proinflammatory cytokines, such as IL-4 and tumor necrosis factor (TNF) α, respectively, can skew naive T cells away from Treg differentiation. Impaired epithelial membrane and cell-cell junctional integrity in asthma, Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) allow for the increased passage of antigen into the subepithelial space, which, in turn, can activate dendritic cells and drive them to promote a proinflammatory state characterized by reduced indoleamine 2,3-dioxygenase (IDO).