IntroductionCompelling evidence indicates that regulatory T (Treg) cells play an important role in the maintenance of immune tolerance to selfand foreign antigens (Ags). [1][2][3] In mice and humans, various subsets of T lymphocytes that have the ability to down-regulate the proliferation of autoimmune effector cells have been isolated. [4][5][6] CD4 ϩ CD25 ϩ T cells are the most extensively studied Treg cells. Eliminating CD4 ϩ CD25 ϩ T cells from the periphery of mice leads to the development of systemic autoimmune diseases, and adding them back can ameliorate experimentally induced autoimmune diseases and graft-versus-host disease after allogeneic bone marrow transplantation. 7,8 Other Treg cells, including CD4 ϩ CD45Rb low , CD4 ϩ DX5 ϩ T cells, 9 CD8 ϩ T cells, 10 T-cell receptor (TCR)␥␦ ϩ cells, 11 and TCR␣ ϩ CD3 ϩ CD4 Ϫ CD8 Ϫ double-negative (DN) T cells 12,13 have also been demonstrated to have a potent role in down-regulating immune responses.The majority of peripheral TCR␣ ϩ CD3 ϩ T cells in normal mice express either CD4 or CD8 molecules. However, approximately 1% to 3% of peripheral CD3 ϩ T cells express TCR␣ but neither CD4 nor CD8 and are thus DN T cells. Strober et al 14 were the first to describe a natural suppressor activity of DN T cells that was not major histocompatibility complex (MHC) restricted. In humans and mice, DN T cells are detected in lymphoid and nonlymphoid tissues (for a review, see Reimann 15 ). Clonal or oligoclonal expansion of DN T cells in humans has been reported in healthy individuals 16 and in patients with either autoimmune diseases 15,17 or combined immunodeficiency with features of autologous graft-versus-host disease. 18 Zhang and colleagues 12 were the first to identify and characterize Ag-specific DN Treg cells. They initially demonstrated, in mice, that DN Treg cells have a unique phenotype that makes the DN Treg cells different from any previously described T cell. They further demonstrated that (1) DN Treg cells, as a novel subset of Treg cells, can specifically down-regulate immune responses toward allo-Ags both in vitro and in vivo 12 ; (2) both primary activated and cloned DN Treg cells can specifically kill activated CD4 ϩ and CD8 ϩ T cells with the same TCR specificity 12,19,20 ; and (3) infusion of in vitro-activated DN Treg cells leads to significant prolongation of donor-specific skin 12 and heart graft survival. 21 Others have shown that DN Treg cells also play an immune regulatory role in autoimmune and infectious diseases. 13 In vitro studies have identified a unique mechanism by which DN Treg cells mediate an Ag-specific suppression of syngeneic responder cells. Studies showed that DN Treg cells can use their TCR to acquire allo-MHC peptides from antigen-presenting cells (APCs) and use them to specifically trap and kill CD4 ϩ or CD8 ϩ T cells that recognize the same allo-MHC peptides through a process that requires cell-to-cell contact and Fas/FasL interaction. 12 Although it has been evident that the DN Treg cell population constitutes a unique li...
Adoptive T cell therapy has been successfully used for treatment of viral and malignant diseases. However, little is known about the fate and trafficking of transferred Ag-specific T cells. Using the tetramer (TM) technology which allows for detection and quantification of Ag-specific CTL, we assessed the frequency of circulating Melan-A-specific CTL in advanced melanoma patients during adoptive T cell therapy. Melan-A-specific CTL were generated from HLA-A2.1+ patients by in vitro stimulation of CD8+ T cells with dendritic cells pulsed with a mutated HLA-A2-binding Melan-A (ELAGIGILTV) peptide. Eight patients received three infusions of 0.25–11 × 108 Melan-A-specific CTL i.v. at 2-wk intervals along with low-dose IL-2. The transferred T cell product contained a mean of 42.1% Melan-A-TM+ CTL. Before therapy, the frequencies of Melan-A-specific CTL in patients’ circulating CD8+ T cells ranged from 0.01 to 0.07%. Characterization of the TM frequencies before and at different time points after transfer revealed an increase of circulating Melan-A-specific CTL up to 2%, correlating well with the number of transferred CTL. An elevated frequency of TM+ T cells was demonstrated up to 14 days after transfer, suggesting long-term survival and/or proliferation of transferred CTL. Combining TM analysis with a flow cytometry-based cytokine secretion assay, unimpaired production of IFN-γ was demonstrated in vivo for at least 24 h after transfer. Indium-111 labeling of Melan-A-specific CTL demonstrated localization of transferred CTL to metastatic sites as early as 48 h after injection. Overall, the results suggest that in vitro-generated Melan-A-specific CTL survive intact in vivo for several weeks and localize preferentially to tumor.
Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8 ؉ T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A 26 -35 peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-␥, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.
No abstract
No abstract
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.