The role of Adenylate Kinase 2 in thymic epithelial cell development and function

Musette, Lucas. The role of Adenylate Kinase 2 in thymic epithelial cell development and function. 2022, Doctoral Thesis, University of Basel, Faculty of Science.

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Reticular Dysgenesis (RD) is a genetic immunodeficiency characterised by severe neutropenia, lymphopenia, thymic and secondary lymphoid organ hypoplasia associated with a high risk for fatal septicaemia within days after birth. RD is caused by a loss of function of the Adenylate Kinase 2 (AK2), an enzyme mainly localised in the mitochondrial intermembrane space that generates ADP via the transfer of a phosphate from ATP to AMP. The only treatment of RD's haematological pathology is a bone marrow transplant that results in generation of donor-derived peripheral T cells. However, the functional capacity of these cells and the thymopoïetic competence of AK2-deficient stromal cells have never been investigated in detail.
The thymus provides a highly organised environment where hematopoietic early thymic progenitors (ETP) differentiate into naïve T-cells. Thymic epithelial cells (TEC) which constitute the major stroma cell type, are essential for this function. Based on morphological, gene expression and functional characteristics, TEC are differentiated into cortical (c) and a medullary (m) epithelial cells. cTEC attract blood-borne ETP, induce their specification to the T-cell lineage, foster their early development and survival and shape their T-cell receptor (TCR) repertoire, together with mTEC thus eliminating thymocytes with a high receptor specificity to self- antigens. To investigate the role of AK2 in TEC function and development, a mouse model lacking Ak2 in a TEC-restricted fashion has been generated.
AK2-deficient mice displayed hypoplastic thymi that correlated with a lower cellularity. Within TEC population, mTEC of knockout mice were severely decreased, resulting in a centrally positioned medulla containing keratin-free zones filled with fibroblasts. Mutant mice also displayed an abundant subpopulation of TEC lacking classical cortical and medullary markers that showed molecular features of immature cTEC. Loss of AK2 affected the energy metabolism of TEC and resulted in an enhanced mitochondrial superoxide content. The augmentation of reactive oxygen species (ROS) contributed to the reduction of mTEC in mutant mice and was likely involved in the increase of number of mitochondria in AK2- deficient cTEC and immature mTEC subpopulations. Thymopoïetic function is negatively affected by the loss of AK2: lower recruitment of T cell progenitors, decreased progression across beta-selection, reduced positive and negative selection and diminished post-selection maturation. Impairment of thymopoïesis resulted in T cell lymphopenia but did not induce overt autoimmunity in mutant mice. Taken together, this work demonstrates that AK2 plays a crucial role in TEC development and function.
Advisors:Holländer, Georg and Hess, Christoph and Schwarz, Klaus
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Pediatric Immunology (Holländer)
05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Bioanalytical Microsystems (Schwarz)
UniBasel Contributors:Holländer, Georg and Hess, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14877
Thesis status:Complete
Number of Pages:v, 106
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss148771
edoc DOI:
Last Modified:01 May 2023 01:30
Deposited On:05 Dec 2022 09:28

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