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The role of coronin 1 in T cell signalling and development

Lang, Mathias Jakob. The role of coronin 1 in T cell signalling and development. 2017, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12219

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Abstract

The immune system of a mammalian organism consists of two major players, the innate and adaptive immune system. While the innate system is used as a first line of defence based on fixed recognition patterns, the adaptive immune system has the capabilities to develop highly specific ways to recognize different pathogens and malignant cells. The main players of the adaptive immune system are B and T lymphocytes. While the major responsibility of a B cell is the production of antibodies, T cells act in a helping (CD4+ helper cells), regulatory (CD4+ regulatory) or killing (CD8+ cytotoxic) manner. The recognition of antigens by T cells is mediated by the T Cell Receptor (TCR), which needs to be modulated and rearranged during T cell development in the thymus. The passage of cells, then called thymocytes, through the thymus is a highly specified and controlled process in which around 95% of thymocytes die. Their death is linked to signals mediated by the TCR, as a thymocyte egressing from the thymus needs to (i) be able to detect and react to foreign antigens while (ii) not reacting upon encountering self-antigens as this could result in auto-immunity. However, thymocytes which have a functional TCR and are either CD4 or CD8 single-positive, have not fully matured yet. They need to modulate various surface expression markers including CD62L, CD69 or CD24, to ensure that they will also be able to egress from the thymus and perform their function in peripheral secondary lymphoid organs such as the spleen and lymph nodes. These modulations take place during the late stages of thymocyte development and also during a transition phase after thymic egress. Those recent thymic emigrant (RTE) cells are a functionally and phenotypically distinct T cell subset, which shows reduced activation but an increased capacity to populate the T cell niche in the organism. As the development from thymocytes to mature naive T cells (MNT) is a complex process, there are various studies published on defective thymocyte or T cell maturation. Interestingly, most of the studies show survival deficits in other cell types as well. Coronin 1 appears to be responsible for survival only in the peripheral T cell population, but not in other cells of the immune system. This WD-repeat domain protein has originally been identified as being important for the intracellular survival of mycobacteria in macrophages. Subsequent studies using gene modified mice lacking coronin 1 have revealed no major roles in other immune cells with the exception of MNT survival. Coronin 1, however, is not only expressed in immune cells, it has a weak expression in excitatory neurons, where it has been shown to be needed for the production of the second messenger cyclic AMP (cAMP). While the cAMP pathway has not been linked to peripheral T cell survival, it has been shown to be involved in thymocyte apoptosis and to be needed for the full activation of a T cell by TCR stimuli. In addition, coronin 1 increases cAMP production in neurons, coronin 1-deficient cells T cells however show increased levels of cAMP. This increase is not only seen in peripheral T cells but also in CD4 and CD8 single-positive thymocytes. Interestingly, the bulk of increased cAMP stems from conventional CD4+ cells in the coronin 1-deficient animals. However, closer examination revealed that membranes from coronin 1-deficient T cells still show reduced production of cAMP, similar to the phenotype seen in neurons, whereas the increased cAMP production is due to the lack of phosphodiesterases present in T cells lacking coronin 1.
This study confirms previous findings that coronin 1 is dispensable for the development of thymocytes using a defined set of surface markers known to be involved in the transition from late stage thymocytes to RTE. Additionally, there no defect was found in the survival of coronin 1-deficient RTE cells in vivo. As T cells are known to behave differently under T cell depleted conditions, newborn animals were used as early development is the only physiological healthy state in which animals are considered to be lymphodepleted. Interestingly, the data suggests a coronin 1-dependent switch after two weeks of age, with T cells numbers steadily increasing in wild-type mice situation but not in coronin 1-deficient animals. To assess if the peripheral lack of T cells was due to the inability of these cells to transduce survival signals, thymocytes in the last stage before egress were sorted and cultured in vitro. Similar to wild-type cells, the coronin 1-deficient thymocytes were capable of surviving on signals mediated via cell-cell contact with antigen-presenting cells such as dendritic cells (DCs) or by cytokines such as interleukin-7 (IL-7).
Taken together, this study shows a spatial and phenotypical elucidation of T cell development upon the deletion of coronin 1 over the first month of mouse life. Additionally it shows that coronin 1 is only needed for the survival of MNT cells but not of cells in earlier stages, as the earlier stages are (i) not decreased in numbers in vivo and (ii) are capable of survival by known pro-survival mechanisms.
Advisors:Pieters, Jean and Finke, Daniela
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)
UniBasel Contributors:Pieters, Jean and Finke, Daniela
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12219
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (118 Seiten)
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:52
Deposited On:04 Oct 2017 14:35

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