Titel: Immunoregulatory capacity of human skeletal muscle cells during a Trypanosoma cruzi infection
Sonstige Titel: Immunregulatorische Kapazität menschlicher Skelettmuskelzellen während einer Trypanosoma cruzi Infektion
Sprache: Englisch
Autor*in: Lehmann, Cari
Schlagwörter: Skeletal muscle cells; PD-1; Pro-inflammatory cytokines; Tim-3; Galectin-9; IL-4I1
GND-Schlagwörter: Trypanosoma cruziGND
Erscheinungsdatum: 2023-09
Tag der mündlichen Prüfung: 2023-12-08
The protozoan parasite Trypanosoma cruzi (T. cruzi) is the causative agent of the potentially life-threatening Chagas disease and leads to lifelong infection. During the infection, T. cruzi-specific cytotoxic CD8+ T cells are necessary for long-term reduction of parasite burden and inflammation. However, in humans with Chagas disease, CD8+ T cells progressively lose function, characterised by decreased cytokine production, advanced differentiation, and increased expression of co-inhibitory receptors. Nevertheless, high levels of pro-inflammatory cytokines, such as IFN-γ and TNF-α, are present throughout the infection, which are mainly secreted by T cells and NK cells. One of the key features of T. cruzi is a chronic infection over the whole lifespan of the host. Especially skeletal muscle cells, were shown to be persistently infected in mice models.
Here, strong evidence is presented that skeletal muscle cells provide a unique niche for T. cruzi by inhibiting clearance of the parasite by CD8+ T cells, thereby allowing the parasite to persist in the body. It could be shown that muscle cells actively shape the immune response. Infected primary human skeletal muscle cells produce immune-recruiting chemokines and cytokines, such as IL-6, IL-8, IL-15 and CCL-19. Furthermore, co-inhibitory receptor ligands, such as PD-L1, PD-L2, galectin-9, HVEM, CD155 and CD122 were expressed by the muscle cells upon stimulation with pro-inflammatory cytokines and infection with T. cruzi. While, the soluble forms of the ligands PD-L1, PD-L2 and galectin-9 are simultaneously found in the supernatant of muscle cell cultures. Proliferation-analysis of CD8+ and CD4+ T cells revealed suppressive capacity of T. cruzi-infected muscle cells in a PD-1 and TIM-3-dependent manner. In line, stimulation of the muscle cells with IFN-γ prior to the co-culture resulted in even higher suppression capacity. High levels of galectin-9 are present in the serum of Chagas patients, indicating a potential systemic inhibition of T cell function. Moreover, the secretion of the IL4-I1 enzyme by muscle cells could be demonstrated. This molecule can upregulate co-inhibitory receptor ligands on T cells, reduce T cell proliferation and induce apoptosis. Thus, IL4-I1 might represent a promising new candidate whose immunoregulatory role during T. cruzi infection needs to be further investigated. In conclusion, multiple mechanisms by which muscle cells can regulate the immune cell response are presented here and indicate that blocking only one of those mechanisms might not be sufficient to augment T cell activity.
Moreover, it was revealed that muscle cells sense the infection with T. cruzi and induce anti-parasitic mechanisms, like the induction of iNOS. This mechanism is capable of significantly reducing the parasite load in muscle cells. The pro-inflammatory environment plays an ambiguous role in the muscle during T. cruzi infection by inducing anti-parasitic mechanisms, thereby reducing parasite burden and at the same time inducing immune regulatory mechanisms, which down-regulate the T cell response. Together, these mechanisms might be essential to ensure limited tissue damage and parasite persistence. Thus, muscle cells prove to be crucial modulators of immune cells during T. cruzi infection.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/10669
URN: urn:nbn:de:gbv:18-ediss-114591
Dokumenttyp: Dissertation
Betreuer*in: Jacobs, Thomas
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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