Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T-Cells following Therapeutic Vaccination

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Abstract

T-cell vaccination may prevent or treat cancer and infectious diseases, but further progress is required to increase clinical efficacy. Step-by-step improvements of T-cell vaccination in phase I/II clinical studies combined with very detailed analysis of T-cell responses at the single cell level are the strategy of choice for the identification of the most promising vaccine candidates for testing in subsequent large-scale phase III clinical trials. Major aims are to fully identify the most efficient T-cells in anticancer therapy, to characterize their TCRs, and to pinpoint the mechanisms of T-cell recruitment and function in well-defined clinical situations. Here we discuss novel strategies for the assessment of human T-cell responses, revealing in part unprecedented insight into T-cell biology and novel structural principles that govern TCR-pMHC recognition. Together, the described approaches advance our knowledge of T-cell mediated-protection from human diseases.

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Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.

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E. John Wherry, Volker Teichgräber, Todd C. Becker … (2003)

Memory CD8 T cells can be divided into two subsets, central (T(CM)) and effector (T(EM)), but their lineage relationships and their ability to persist and confer protective immunity are not well understood. Our results show that T(CM) have a greater capacity than T(EM) to persist in vivo and are more efficient in mediating protective immunity because of their increased proliferative potential. We also demonstrate that, following antigen clearance, T(EM) convert to T(CM) and that the duration of this differentiation is programmed within the first week after immunization. We propose that T(CM) and T(EM) do not necessarily represent distinct subsets, but are part of a continuum in a linear naive --> effector --> T(EM) --> T(CM) differentiation pathway.

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Inferences, questions and possibilities in Toll-like receptor signalling.

Bruce Beutler (2004)

The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.