The surface atlas of human naive and activated CD4+ T cells

Gräßel, Anke (2016): The surface atlas of human naive and activated CD4+ T cells: characterization of early T cell activation on a multi-omic level. Dissertation, LMU München: Fakultät für Biologie

Abstract

Naive CD4+ T cells are the precursor cells of all effector T helper cell subsets and they form the basis of the immunologic memory. These cells provide one of the earliest cellular targets to modulate T cell activation and differentiation during the development of CD4+ T cell driven immune pathologies such as autoimmune diseases and allergies, which are an in-creasing problem for the worlds’ societies. Easy accessible cell surface proteins are responsi-ble for the recognition of and response to signals of other cells or changes in the environ-ment, therefore, they can be described as interesting targets for immune modulation strate-gies such as immunotherapy and vaccination. The aim of this dissertation is to characterize the proteomic cell surface composition of human naive CD4+ T cells and their changes during T cell activation on a multi-omic level to deepen the current knowledge about these im-portant immune cells and to identify new immune targets for the development of novel im-mune modulation strategies. Human naive CD4+ T cells were isolated and activated with an-ti-CD3/anti-CD28 in a time course experiment to mimic T cell receptor engagement. The samples were analyzed via a non-targeted proteomic technique (PAL-qLC-MS/MS), a target-ed flow cytometry screen and a genome-wide microarray expression analysis coupled to bioinformatics analyses. All obtained results were combined in the surface atlas of human naive and activated CD4+ T cells. Out of the analyzed multi-omic datasets, the transmem-brane protein c16orf54 was chosen for further investigations and tools such as monoclonal antibodies, stable expression systems and murine model organisms were generated. 229 cell surface proteins were identified and quantified on human naive and activated CD4+ T cells by the proteomic techniques and 927 cell surface protein coding transcripts were detected by the transcriptomic analyses. 51 of the cell surface proteins are annotated as targets for ap-proved drugs and further interesting cell surface targets such as solute carrier transport pro-teins and proteins, which were not described in the context of T cell biology before, like the transmembrane protein c16orf54, were identified by analyses of the multi-omic datasets. Newly generated investigational tools revealed that c16orf54 is not only expressed on naive and activated CD4+ T cells within the compartment of immune cells in the blood. The generated surface atlas of human naive and activated CD4+ T cells can be seen as multi-omic reference guide for CD4+ T cell activation, increasing the current knowledge of CD4+ T cell biology. In addition, it provides a rich source of interesting immune targets, which can be investigated in the context of novel therapeutic strategies aiming to modulate reactions of the immune system during the development of CD4+ T cell driven diseases.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: T cells, -omics, cell surface proteome
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 12. Juli 2016
• 1. Bericht­erstatter:in: Grothe, Benedikt