Mechanisms regulating autoreactive T cell responses in inflammatory heart disease

Abstract

Molecular self-assembly, as a most studied case of self-assembly, is one of the few practical strategies for making ensembles of nano- and micro structures. As an essential aspect of the “bottom-up” approach, it is attractive for both scientific research and technological applications. Therefore a detailed understanding of the molecule-substrate and intermolecular interactions involved in the self-assembly process is of great interest. In the first part of the thesis, the influence of the phenoxy substituents on the self-assembly of Pcs on (111)-oriented noble metal surfaces is described. The rotational degrees of freedom, characteristic for these substituents enable the formation of various stable and transient phases and allow the substituents to be arranged above the plane of the Pc core, forming a bowl-like structure, which in turn enables the interaction of the Pc core with the metal substrate. The proximity of the Pc core to the metal substrate together with the steric entanglement between neighboring substituents causes significant retardation of the thermodynamic optimization of the conformations. This accounts for the coexistence of some of the phases. In the second part, the influence of replacing two adjacent phenoxy substituents by a rigid tetraazatriphenylene substituent on the self-assembly of Pcs is analyzed and compared to the self-assembly of the above mentioned phenoxy substituted Pcs. The rigid substituent enhances the rotational degrees of freedom of the neighboring phenoxy substituents, hence facilitates their conformational optimization. As a result, novel interactions between the Pc derivatives are enabled and the formation of ordered phases with higher surface densities compared to the previous study is observed. In the third part, the hosting properties of a close-packed layer of phenoxy substituted Pc derivatives adsorbed on Ag(111) are investigated for the adsorption of C60 molecules. The C60 molecules bind to two clearly distinguishable sites, either to the underlying metal substrate in between two adjacent Pc derivatives or to the core of a Pc derivative. In the first case, the C60 exhibit morphologic and electronic properties analogous to those of a C60 adsorbed on clean Ag(111), whereas in the second case the electronic properties indicate a strong interaction between C60 and the phthalocyanine core. produce the short living molecule nitric oxide, which is able to reversibly inhibit T cell proliferation. In vivo, serial injections of wt CD11b+ monocytes into diseased IFN-!R-/- mice were sufficient to provide a good number of functional CD11b+ monocytes to block EAM in high susceptible IFN-!R-/- mice. Dendritic cells subsets differently regulate autoimmunity. In fact, bone marrow-derived dendritic cells (bmDC) promoted IL-17-mediated EAM, while splenic CD+ dendritic cells were slightly pathogenic and induced low levels of EAM. CD8+ DC stimulated with LPS-CD40, producing high levels of IL- 1# and IL-6, induced the development of auto-aggressive IL-17-producing CD4+ Th17 cells, while TNF--stimulated CD8+ DC polarized IFN-!- producing CD4+ Th1 cells. The potential of CD8+ DC to induce protective IFN-!-producing T cells was used to develop a vaccination strategy. Indeed, mice vaccinated with serial injections of self-peptide-loaded and TNF-- stimulated CD8+ DC showed an increased production of IFN-! by selfpeptide- specific CD4+ T cells and were protected from EAM. Taken together, the opposite roles of IFN-! as protective cytokine and IL-17 as inflammatory cytokine have been further explained in EAM.