Role of the chemokines CCL17 and CCL22 in bacterial infection and IL-33-induced immune responses

Abstract

The chemokines CCL17 and CCL22 are primarily expressed by dendritic cells (DC) and macrophages. Both chemokines share the receptor CCR4, which is expressed on DC and macrophages as well as on a variety of different T cell subsets, including T_h1 cells, T_h2 cells, and regulatory T (T_reg) cells. As ligands of CCR4, CCL17 and CCL22 recruit T cells, facilitate the T cell-DC interaction, and sensitise DC for migration. However, CCL17 and CCL22 differ in their distinct signaling pathways and functions, a phenomenon that has been termed biased agonism. CCL17 is involved in the induction and enhancement of numerous allergic and inflammatory diseases. In contrast, CCL22 is rather associated with an immunosuppressive environment. Moreover, CCL17 induces migration and activation of T_h1 and T_h2 cells as well as sensitising DC migration towards CCR7-ligands, whereas CCL22 facilitates the recruitment of Treg cells. In addition, CCL22 shows higher receptor-binding affinity and induces desensitisation and internalisation of CCR4 more rapidly than CCL17. Although CCL17 and CCL22 were extensively studied in allergic, inflammatory, and autoimmune diseases as well as in the tumor microenvironment, their involvement in infectious diseases has not been well described. Furthermore, IL-33 stimulates the production of CCL17 and CCL22 by DC. In the context of <em>Salmonella</em> infection, IL-33 can be produced by intestinal stroma cells after stimulation with bacterial ligands and IL-33 secretion by pericryptal fibroblasts was shown to be directly protective against the infection. Hence, the aim of this thesis was to elucidate the differential function of CCL17 and CCL22 in the context of <em>Salmonella</em> infection and IL-33-mediated immune responses in organs linked to <em>Salmonella</em> dissemination and beyond. <br /> Using a vaccination/challenge <em>Salmonella</em> mouse model, wt, CCL17^E/E CCL22^-/-, and CCR4^-/- mice were investigated for their antigen-specific CD4⁺ T cell response. Vaccinated CCL17^E/E CCL22^-/- and CCR4^-/- mice were less protected against <em>Salmonella</em> challenge, while vaccinated wt mice survived with 100 %, potentially suggesting an impaired recruitment or positioning of CD4⁺ T cells and a subsequent defect in clearing the infection. <br /> In the context of IL-33-mediated immune responses, CCL22 appeared to play a detrimental role in IL-33-induced adipose tissue fibrosis as adipose tissue morphology XII exhibited less signs of inflammation, indicated by fibrosis and immune cell infiltration, in CCL22-deficient mice. Moreover, CCL17 and CCL22 were involved in adipose tissue homeostasis in the inguinal white adipose tissue as well as the brown adipose tissue in the case of CCL22. Absence of CCL17, CCL22, and CCR4 caused eosinophilia in the blood, potentially due to an impaired recruitment of eosinophils from the bloodstream into the tissue. Additionally, while IL-33 impaired bone marrow erythropoiesis independently of the CCL17/CCL22/CCR4-axis and thereby caused extramedullary erythropoiesis in the spleen, CCL22 promoted the expansion of basophilic erythroblasts in the spleen. <br /> Lastly, comparison of CCL17^E/E CCL22^-/- and CCR4^-/- mice revealed certain phenotypic differences, suggesting the existence of a second receptor for CCL17 and CCL22. Using a chemokine-based receptor staining approach, it was confirmed that CCR4-deficient T cells in the thymus and spleen were still able to bind both chemokines. A putative second receptor, however, was not involved in mediating chemotaxis as CCR4-deficiency abrogated migration of primary T cells from the thymus and of the T cell lymphoma cell line BW5147.3. <br /> In conclusion, uncovering both protective and detrimental functions of CCL17 and CCL22 as well as an additional player in the CCL17/CCL22/CCR4-axis opens new aspects to consider in future applications, disease studies and even therapeutically approaches.