Universität Tübingen
Unconventional T lymphocytes - recombinant MHC molecules pave the way
Abstract
T cells are central orchestrators and effectors of the adaptive immune system. CD8+ T cells that recognize peptide antigens presented on MHC class I molecules are believed to play a central role in fighting viral infections, intracellular pathogens and cancer. The use of recombinant peptide-HLA class I complexes that mimic the natural ligands of human CD8+ T cells should greatly facilitate the manipulation and analysis of such cells, allowing further insight in their biology and opening therapeutic applications. To permit the rapid access to cytotoxic CD8+ T cells with defined properties, artificial antigen presenting cells with defined MHC densities were devised that enable in vitro priming of high- or low-avidity effector T cells at will. High-avidity T cells required more stringent costimulatory conditions during priming but were clearly superior in recognizing tumor cells expressing antigen. The efficiency and high degree of control of such a system may be of great potential for future immunotherapeutic settings. Using fluorescent MHC I multimers to analyze T-cell responses during infection and in healthy individuals, it was found that these tools allow the detection of unconventional T cells that would have remained unidentified by the use of conventional methods. First, in a patient with congenital CMV infection, it was found that circulating functional CD4+ and CD8+ T cells specific for the same viral peptide bound to an HLA class I molecule can coexist. This unexpected finding will extend the view of T-cell responses against viral antigens and poses questions on the role of MHC class I restricted CD4+ T cells in vivo. Finally, the detailed ex vivo characterisation of another unexpected cell population was reported. These CD8+ T cells, found in a significant proportion of healthy HLA-A2+ donors, are apparently specific for a peptide from the self-protein cytokeratin 18. Albeit showing the phenotypical hallmarks of antigen-experienced effector CD8+ cells, these cells did neither lyse cognate target cells nor did they express any tested cytokine upon antigen recognition. These findings suggest that the subset of circulating human CD8+ T cells with the effector phenotype may be more heterogenous than previously thought and comprise cells without classical effector function and so far with unknown function.
Author and committee
dc:creator, dc:contributor.*- Author
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- Walter, Steffen
Identifiers
dc:identifier.*- Identifier
- hdl:10900/43844