The role of the chemokine CCL22 in the interaction of dendritic cells and regulatory T cells

Kunz, Wolfgang (2017): The role of the chemokine CCL22 in the interaction of dendritic cells and regulatory T cells. Dissertation, LMU München: Medizinische Fakultät

Abstract

Immune tolerance by regulatory T cells (TReg) requires continuous interactions with dendritic cells (DCs) to screen the organism for potentially harmful self-antigen presentation. Ultimately, this interaction keeps effector T cells (TEff) with auto-reactive properties in check as the contact with DCs, TReg and cognate antigen induces anergy, a state of non-responsiveness. The efficient collaboration of these three immune cell types therefore dictates the delicate balance between immunity and tolerance. The aim of this study was to investigate the role of the chemokine CCL22 as a mediator of DC-TReg interactions. Based on previous observations of CCL22-dependent migration of CCR4+ TReg and CCL22 production by DCs, we hypothesized that CCL22 recruits TReg to DCs and increases their interaction frequency. Therefore, I investigated DC-TReg interactions in vitro and in vivo. In addition, I studied the influence of innate and adaptive immune stimulation on CCL22 and CCR4 expression. I showed that DC-TReg interactions were significantly more frequent in vitro and in vivo for DCs that secreted CCL22 compared to DCs that did not secrete CCL22. In vivo, I studied dynamic interactions in peripheral lymph nodes by intravital microscopy and observed longer antigen-dependent DC-TReg contact times for DCs that secreted CCL22. These results suggest that the homeostatic production of CCL22 by DCs serves as a signal to recruit TReg to support continuous immune tolerance during the steady state. Studying the influence of the innate immune system on the CCL22-CCR4 axis, I observed a decrease of CCR4 expression by TReg after stimulation with TLR and RLR ligands. In contrast, adaptive immune responses in the form of cognate-antigen DC-TEff interactions led to strong and rapid induction of CCR4 expression by TReg and further to CCL22 production by DCs. This strong induction following cognate-antigen interaction with TEff might represent a mechanism of immune surveillance, as more TReg will be recruited to the DCs that interact with TEff. These new mechanistic insights advance our comprehension of TReg function and may help to make use of their enormous potential in clinical applications for autoimmune diseases, for cancer and beyond.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Regulatory T Cells, TReg, Chemokine, Migration, Intravital Imaging
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. Oktober 2017
• 1. Bericht­erstatter:in: Anz, David