Functions and memory features of adaptiveand innate immune cells in physiological and inflammatory settings

Abstract

The immune system is a complex but well-regulated network which cooperates with the microbiota to maintain optimal homeostasis under physiological settings. A number of factors display the capacity to alter the immune system and thus microbiota crosstalk including host genetics, diet, environmental influences and drugs such as antibiotics or chemotherapeutic agents.

We and others have previously demonstrated immune regulatory capacities of the gut commensal Limosilactobacillus reuteri (L. reuteri) that seem to act via myeloid cells. In paper I, we have further shown that priming of blood dendritic cells (DCs) or monocytes with L. reuteri-derived cell free supernatant (CFS) modifies how these cells respond to future stimulus challenge, even after monocytes differentiation to DCs (mo-DCs). Notably, priming conditions in mo-DCs skewed subsequent T-helper cell responses. In paper II, we continued to elaborate on whether microbial and gutassociated metabolites modify chemotherapy-induced effects. Thus far, we could show that the CFS from probiotic bacteria might imprint immune cells to modulate inflammatory responses when intestinal epithelial cells are compromised by chemotherapy exposure. In paper III, we investigated how chemotherapy agent Doxorubicin (Doxo) affects bone marrow resident mesenchymal stromal cells (BM MSCs) which support antibody secreting cells (ASCs) responsible for serological memory. Our findings have shown that Doxo-induced alterations in BM MSCs are not sufficient to disrupt their support to ASCs, thus alternative or additional factors might be implicated in ASC preservation during chemotherapy. Lastly, in paper IV, we investigated how Doxo affects secondary lymphoid organs and we found that splenic compartment is more prominently affected by Doxo treatment compared to its lymph node counterpart in an animal model of rhesus macaques.

Collectively, this thesis outlines novel perceptions on innate immune memory-like capacity and how gut-associated factors influence such recall responses in innate immune cells. Further, this thesis increases our knowledge on how adaptive immune cells, required for long-term serological memory, are preserved during toxic conditions such as those induced by chemotherapy treatment.

Keywords: Innate immune memory, Limosilactobacillus reuteri, dendritic cells, lymphocytes, cytokines, immunological memory, intestinal epithelial cells, chemotherapy, bone marrow, secondary lymphoid organs.