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γδ T cells and γδ T cell receptors in tumor-immunotherapy

Thursday 17 January 2013

Dr. Jürgen Kuball

Dissecting graft-versus-host disease from graft-versus-leukemia effect following allogeneic stem-cell-transplantation remains a major goal in ongoing research efforts. One attractive possibility to selectively mediate anti-leukemia-activity arises from the ability of gδT-cells to mediate anti-leukemia-reactivity while ignoring allogeneic-environment. The gδT-cell-receptor (TCR) itself can mediate this intriguing property. To test the ability of gδTCRs to mediate anti-leukemia-reactivity while ignoring allogeneic-environment, our laboratory has previously cloned a variety of gδT-cells and their TCRs. By TCR-gene-transfer-experiments we confirmed that a gδTCR mediates anti-leukemia-reactivity and ignores allogeneic-environment. The redirection of T-cells against leukaemia-cells by transfer of a gδTCR is therefore a promising new strategy to selectively redirect the immune-system against leukemias. However, the limited knowledge about molecules/proteins recognized by gδTCRs makes it difficult to rationally design such therapies and further identification of gδTCR-ligands are therefore needed. This knowledge would not only allow rational design of the proposed experimental therapy, but also shed light into recognition-mechanisms of transformed and infected cells by the innate-immune-system and therefore have fundamental impact far beyond the mentioned clinical implication. To identify potential ligands of cloned gδTCRs we the Master Student will work on the following project: Comparative-proteomics of defined targets: Multiple leukemia-reference-cell-lines are recognized by the so far cloned γδTCR while others are not. Furthermore, recognition of ignored malignant cell lines can be induced by bisphosphonates. In order to determine proteins that are directly or indirectly involved in recognition of the leukemia-cells by a γδTCR, we will isolate total proteins and surface proteins of different reference-cell-lines and compare protein-expression-profile of recognized cell-lines to the protein-expression-profile in ignored cell-lines. Proteins that are selectively expressed in recognized cell-lines will be sequenced. In future studies we aim to further characterize here-identified proteins. This includes but is not limited to confirming binding of the TCR to identified proteins by Biacore-analysis, characterizing the role of these proteins in leukemogenesis, and analyzing expression of defined proteins in primary leukemia-(stem)-cells

Molecular biology: PCR, western blot, proteomics
Cell biology: T cell culture, T cell cloning, functional analysis of T cells

6 or 9 months

Dr Jürgen Kuball, tel. 088 75 549 82, j.h.e.kuball@umcutrecht.nl
Dr Kristin Denzer, tel. 088 75 643 68, k.denzer@umcutrecht.nl