Key Points We describe a novel allo-tumor–reactive and CD8α-dependent Vγ5Vδ1TCR. The molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 is an essential determinant of recognition.
T cell epitopes derived from polymorphic proteins or from proteins encoded by alternative reading frames (ARFs) play an important role in (tumor) immunology. Identification of these peptides is successfully performed with mass spectrometry. In a mass spectrometry-based approach, the recorded tandem mass spectra are matched against hypothetical spectra generated from known protein sequence databases. Commonly used protein databases contain a minimal level of redundancy, and thus, are not suitable data sources for searching polymorphic T cell epitopes, either in normal or ARFs. At the same time, however, these databases contain much non-polymorphic sequence information, thereby complicating the matching of recorded and theoretical spectra, and increasing the potential for finding false positives. Therefore, we created a database with peptides from ARFs and peptide variation arising from single nucleotide polymorphisms (SNPs). It is based on the human mRNA sequences from the well-annotated reference sequence (RefSeq) database and associated variation information derived from the Single Nucleotide Polymorphism Database (dbSNP). In this process, we removed all non-polymorphic information. Investigation of the frequency of SNPs in the dbSNP revealed that many SNPs are non-polymorphic “SNPs”. Therefore, we removed those from our dedicated database, and this resulted in a comprehensive high quality database, which we coined the Human Short Peptide Variation Database (HSPVdb). The value of our HSPVdb is shown by identification of the majority of published polymorphic SNP- and/or ARF-derived epitopes from a mass spectrometry-based proteomics workflow, and by a large variety of polymorphic peptides identified as potential T cell epitopes in the HLA-ligandome presented by the Epstein–Barr virus cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-010-0497-1) contains supplementary material, which is available to authorized users.
Electrophoretically pure human interleukin-1 (IL-1) beta was found to stimulate human fibroblasts in a monolayer culture to elaborate colony- stimulating activity (CSA). Supernatant fluids from cultures induced with increasing concentrations of IL-1 were found to stimulate colony formation of myeloid (CFU-GM), erythroid (BFU-E), and multipotent (CFU- GEMM) progenitor cells in a dose-dependent fashion. The effect on mixed colony formation, however, was less than on CFU-GM and BFU-E growth. Similar to IL-1, the synthetical double-stranded RNA poly(rI).poly(rC) also stimulated release of CSA by fibroblasts. The kinetics of IL-1- and poly(rI).poly(rC)-induced CSA release were found to be different, in that poly(rI).poly(rC)-induced CSA production occurred more slowly. Anti-IL-1 antiserum was able to completely neutralize the IL-1-induced CSA release, but had no effect on poly(rI).poly(rC)-induced CSF production, suggesting that the latter effect was mediated by other mechanisms than IL-1 in supernatant. By the use of specific immunologic assays, G-CSF, M-CSF, and GM-CSF could be identified in media conditioned by fibroblasts treated with IL-1 or poly(rI).poly(rC). Poly(rI).poly(rC) appeared to be a better inducer for M-CSF than IL-1.
T cells against self-antigens can be detected in peripheral blood of healthy individuals, although intrathymic negative selection removes most high-avidity T cells specific for self-antigens from the peripheral repertoire. Moreover, spontaneous T-cell proliferation following stimulation with autologous monocyte-derived dendritic cells (autoDCs) has been observed in vitro. In this study, we characterized the nature and immunological basis of the autoDC reactivity in the T-cell repertoire of healthy donors. We show that a minority of naive and memory CD4 + T cells within the healthy human T-cell repertoire mediates HLA-restricted reactivity against autoDCs, which behave like a normal antigen-specific immune response. This reactivity appeared to be primarily directed against myeloid lineage cells. Although cytokine production by the reactive T cells was observed, this did not coincide with overt cytotoxic activity against autoDCs. AutoDC reactivity was also observed in the CD8 + T-cell compartment, but this appeared to be mainly cytokine-induced rather than antigen-driven. In conclusion, we show that the presence of autoreactive T cells harboring the potential to react against autologous and HLA-matched allogeneic myeloid cells is a common phenomenon in healthy individuals. These autoDC-reactive T cells may help the induction of primary T-cell responses at the DC priming site. Keywords: Autologous responses r CD4 + T cells r Dendritic cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAutologous or allogeneic T-cell responses against antigens that are either selectively expressed or overexpressed on malignant cells compared to normal cellular counterparts (tumor-associated antigens (TAAs)) are generally assumed to play an important role in immune surveillance against cancer and in cellular immunotherapy strategies [1][2][3][4][5]. In autologous and HLA-matched Correspondence: Dr. Inge Jedema e-mail: I.Jedema@lumc.nl allogeneic stem cell transplantation settings, these antigens will be presented and recognized in the context of self-HLA molecules on the cell membrane. When self-antigens and TAAs are expressed in the thymus, potentially harmful T cells expressing a highaffinity T-cell receptor (TCR) specific for these self-antigens or TAAs in the context of self-HLA are deleted from the Tcell repertoire during negative selection [6,7]. This impedes not only induction of autoimmunity but also antitumor immunity, thereby weakening the concept of functional immune surveillance against malignant cells in the autologous and HLAmatched setting. However, immune responses against autologous malignant cells have frequently been observed, although the functional avidity of these T cells may often be questionable [8][9][10][11][12][13].In line with the observations of autologous tumor-reactive T-cell responses, proliferation of (naive) T cells in response to autologous monocyte-derived dendritic cells (autoDCs) has also been demonstrated in in vitro ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.