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Hematopoietic stem cells - active modulators of immunity and hematopoiesis in health and disease

Hernández Malmierca, Pablo

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Abstract

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the life-long production of mature blood and immune cells. These mature cells perform a wide variety of function in the body, from oxygen distribution to defense against external and internal threats. Within the immune system, adaptive immune cells are capable of mounting a highly specific immune reaction against unique pathogenic epitopes. To accomplish this distinctive feature, antigens are presented to T cells by the major histocompatibility complexes (MHC). While MHC class-I (MHC-I) is expressed on the majority of cells and activates CD8+ T cells, CD4+ T cell-activating MHC-II is exclusively expressed by specialized antigen presenting cells (APCs). In fact, antigen presentation via MHC-II to CD4+ T cells constitute the central process in the orchestration of adaptive immune responses. The data in this thesis uncovered that HSPCs are not only passive receivers of immunological signals but act as antigen presenting cells capable of functionally modulating CD4+ T cells and thus, their immune microenvironment. First, we demonstrated that mouse and human HSPCs express MHC-II at transcript and protein levels. Subsequently, we showed that HSPCs can process and present endogenous and exogenous antigens via MHC-II. Antigen presentation to CD4+ T cells resulted in an efficient T cell activation and immunoregulatory polarization. In detail, these T cells adapted a type 1 regulatory T cell (Tr1)-like state, were capable of suppressing bystander T cells and polarized macrophages into an immunoregulatory state via IL-10. Importantly, HSPCs were induced into cell cycle and myeloid differentiation upon antigen-specific interaction with CD4+ T cells ex vivo and in vivo. Furthermore, sustained antigen presentation promoted HSPC exhaustion. In acute myeloid leukemia (AML), a hematopoietic malignancy derived from HSPCs, an immature phenotype resembling stem cells correlated with higher MHC-II expression and adverse prognosis. HSC-derived AMLs maintained the CD4+ T cell activation ability. Moreover, HSC exhaustion upon extended antigen presentation protected the organism from AML onset. In summary, the first part of this thesis unveils a previously unknown interaction of HSCs with CD4+ T cells. This interaction induces a tolerance mechanism promoting immune suppression within the bone marrow. Last but not least, the immunosuppressive HSPC-T cell interaction proves to be an immune-mediated protection against AML onset. Leukemogenesis is a complex process in which a stepwise acquisition of mutations transforms healthy HSPCs into pre-leukemic and, subsequently, into leukemic cells. Leukemic stem cells (LSCs), similar to their healthy counterparts, are resistant to conventional therapy and responsible for AML relapse. However, current methods do not enable a distinction and systematic comparison between healthy and (pre-)leukemic cell states. Thus, in the second part of this thesis, a method that overcomes this hurdle, MutaSeq, was co-developed. MutaSeq exploits known mutations in AML samples and combines them with mitochondrial variations in order to map the clonal relationships of single cells. Based on the mutational profile, MutaSeq classifies cells as healthy, pre-leukemic or leukemic. Additionally, cell type identity is inferred from transcriptomic data. Lastly, healthy, pre-leukemic and leukemic HSCs can be molecularly compared to identify potential druggable targets. Taken together, the second part of this thesis describes a novel methodology for a systematic distinction and comparison between healthy, pre-leukemic and leukemic HSCs. Further characterization of AML using such type of approaches will increase the chances to effectively target LSCs and thus, avoid AML relapse and enhance patient survival. In summary, this thesis has defined a to date unknown function of HSCs orchestrating the immune system with far reaching implications in health and disease. In addition, a new single cell technology is described to better distinguish and explore the functional differences between healthy pre- and leukemic HSC.

Item Type: Dissertation
Supervisor: Trumpp, Prof. Dr. Andreas
Place of Publication: Heidelberg
Date of thesis defense: 14 September 2021
Date Deposited: 24 Sep 2021 08:57
Date: 2022
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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