Differential role of DGKζ in the control of bone marrow homeostasis and the onset of aplastic anemia

• Autores: Miguel Martín Salgado
• Directores de la Tesis: Isabel Mérida De San Román (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2025
• Idioma: inglés
• Número de páginas: 215
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • T lymphocytes are essential components of the immune response. Recognition of the antigen by the T cell receptor (TCR) triggers a series of early events that culminate with the activation of phospholipase C gamma (PLCγ) and the generation of diacylglycerol (DAG), which together with other molecules, favors the complete activation of the T cell. In this process, additional signals such as costimulatory or cytokines are of essential importance. In the same way as the ignition mechanisms, the shutdown mechanisms are also key. In this context, diacylglycerol kinases (DGKs), a family of lipid enzymes act as negative regulators of T cell activation by catalyzing the conversion of DAG into phosphatidic acid (PA). Of the 10 isoforms described in mammals, two of them, DGKα and DGKζ, are the most abundant in T lymphocytes, where they exert specific and redundant functions in the maintenance of tolerance and the prevention of autoimmune syndromes. Studies in aplastic anemia (AA) patients correlate the lower expression of DGKζ in bone marrow (BM) derived T lymphocytes with the severity of the disease. Those studies prompted us to carry out an in-depth characterization of the BM of DGKζ deficient mice. Our analysis identifies the BM of DGKζ deficient mice as a niche for infiltration of activated T cells. Furthermore, we describe defects in hematopoietic differentiation that suggest a specific function of DGKζ in the control of the differentiation cascade. The absence of good preclinical AA models makes the DGKζ deficient mouse a good system for the study of molecular factors that predispose to the disease. Additionally, we studied the role of DGKζ in the control of the response to interleukin (IL-) 15, a cytokine that is very abundant in the BM and of which incorrect signaling can contribute to autoimmune processes. Our results suggest that the absence of DGKζ results in cytotoxic responses after treatment with IL-15 both in vivo and in vitro. Likewise, we identified the proteins involved in IL-15-mediated signaling, making PLCγ one of the essential elements in this process. Finally, we demonstrate how the activation phenotype previously described in the BM is abrogated in mice deficient for DGKζ and IL-15. With all this, this doctoral thesis focuses on demonstrating the differential role of DGKζ in the maintenance of homeostasis in the BM and how its deficiency can lead to loss of tolerance in the presence of signals capable of mobilizing DAG