Publikationsserver der RWTH Aachen University
The characterization of major histocompatibility complex class II signal transduction pathways in antigen presenting cells
Abstract
dc:descriptionMajor histocompatibility complex class II (MHC-II) molecules, which can be broken down into three different human isotypes, HLA-DR, HLA-DP, and HLA-DQ, are expressed on a wide range of immune cells including B lymphocytes, monocytes/macrophages and dendritic cells. Although MHC-II molecules are well-known for their ability to present antigens to helper T cells, MHC-II molecules can also contribute to signaling pathways that govern the function and survival of antigen presenting cells. Not all signaling pathways linked to MHC-II molecules have been identified, and therefore the major goal of this work is to further characterize the pathways initiated by MHC-II ligation. MHC-II-induced signaling pathways involve a combination of different kinases and transcription factors that lead to different cellular responses such as proliferation, differentiation, and apoptosis. These signaling components were further characterized and new pathways were identified by activating MHC-II molecules with anti-MHC-II antibodies and superantigens. This dissertation examines MHC-II-mediated calcium mobilization and demonstrates that it is an isotype-independent event, which leads to the dephosphorylation of NFAT. In addition, MHC-II molecules work in conjuction with the B cell receptor to increase NFAT activity. As opposed to calcium mobilization, the classical MAP kinases are activated in an isotype-specific manner where only ligation of HLA-DP and HLA-DQ lead to ERK1/2 and MEK1/2 phosphorylation, which corresponds with an increase in c-Fos protein expression and AP-1 dimer formation. MHC-II most likely requires one signaling partner for the activation of tyrosine kinases leading to calcium mobilization and NFAT dephosphorylation and a different signaling partner for triggering the MAP kinase cascade, whereby the restriction of HLA-DR with the cytoskeleton prevents HLA-DR from associating with the signaling partner. Two important cellular responses were also examined including apoptosis and immunoglobulin synthesis. Apoptosis could only be initiated by crosslinking MHC-II molecules with whole antibodies or Fabs crosslinked with a secondary antibody. MHC-II-mediated cell death was found to occur in an ERK1/2-independent manner. Immunoglobulin synthesis was dramatically reduced after superantigen binding, and this can be explained through the loss of B cells by T cell activation. Anti-MHC-II antibodies can also reduce antibody production, but this cannot be attributed to a decrease in viable B cells. Instead, anti-MHC-II antibodies prevent pokeweed mitogen from carrying out its function in differentiating naïve B cells into plasma antibody-secreting B cells. The novel discovery of the activation of NFAT by MHC-II may also explain the change in antibody production during the differentiation of B lymphocytes. Altogether, this work expands upon known signaling mechansisms as well as illustrates new signaling pathways generated by ligating MHC-II molecules. Extending our understanding on MHC-II-mediated signaling can help provide new therapeutic tools for the fields of cancer, autoimmunity, and transplantation therapy.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2009
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Haylett, Romney S.
- Contributors dc:contributor
-
- Rink, Lothar
Subjects
dc:subject × 8Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng