Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells
Jeffrey J. Molldrem, … , Changqing Wang, Mark M. Davis
Jeffrey J. Molldrem, … , Changqing Wang, Mark M. Davis
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):639-647. https://doi.org/10.1172/JCI16398.
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Article Immunology

Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells

Abstract

We have shown that cytotoxic T lymphocytes specific for PR1, an HLA-A2–restricted nonopeptide derived from proteinase 3, kill leukemia cells and may contribute to the elimination of chronic myelogenous leukemia (CML) after treatment with IFN or allogeneic bone marrow transplant. Some patients with persistent disease also have circulating PR1-specific T cells, however, suggesting the likelihood of immune tolerance. Here we show that both high- and low-avidity PR1-specific T cells from the peripheral blood of healthy donors can be identified and selectively expanded in vitro. Although high-avidity PR1-specific T cells killed CML more effectively than low-avidity T cells, only high-avidity T cells underwent apoptosis when stimulated with high PR1 peptide concentration or when exposed to leukemia that overexpressed proteinase 3. No high-avidity PR1-specific T cells could be identified or expanded from newly diagnosed leukemia patients, whereas low-avidity T cells were readily expanded. Circulating high-avidity PR1-specific T cells were identified in IFN-sensitive patients in cytogenetic remission, however. These results provide evidence that CML shapes the host immune response and that leukemia outgrowth may result in part from leukemia-induced selective deletion of high-avidity PR1-specific T cells.

Authors

Jeffrey J. Molldrem, Peter P. Lee, Shreya Kant, Eric Wieder, Weidong Jiang, Sijie Lu, Changqing Wang, Mark M. Davis

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Figure 1

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Lower doses of PR1 peptide induce CTLs with higher intensity PR1/HLA-A2 ...
Lower doses of PR1 peptide induce CTLs with higher intensity PR1/HLA-A2 tetramer staining that correlates with TCR avidity and inversely with effector function threshold. (a) PBMCs collected from healthy HLA-A2.1+ donors were stimulated weekly with PR1 peptide-pulsed T2 cells at the peptide concentrations indicated above each FACS plot. After 4 weeks, resulting cultures were stained with CD8 (FITC) Ab and PR1/HLA-A2 tetramer, and the percentage of CD8+ cells that stain with tetramer are noted within each FACS plot. (b) Surface HLA-A2 expression on T2 cells increases linearly with increasing concentration of PR1 peptide from 2 μM and 200 μM. T2 cells were incubated with PR1 peptide at the concentrations shown and surface HLA-A2 expression was measured by flow cytometry. (c) CTLs elicited with PR1 at 0.2 μM (open circles) or 20 μM (filled squares) PR1 were incubated for 4 hours at 37°C with PR1 peptide-pulsed T2 cells at the indicated peptide concentrations at an effector/target (E/T) ratio of 10:1 (adjusted based on the number of tetramer-positive CTLs), and percentage of specific lysis was determined. (d) Tetramer decay (t1/2) was determined to be 58 minutes and 19 minutes by plotting normalized antigen-specific fluorescence at the indicated time points for 28-day-old PR1/HLA-A2 tetramer-stained CTLs elicited with 0.2 μM (open circles) or 20 μM PR1 (filled squares), respectively. Dissociation kinetics of PR1/HLA-A2 tetramer staining were determined at 4°C in the presence of saturating concentrations of BB7.2 Ab to prevent rebinding of tetramer and in the presence of PI (1 μg/ml) to eliminate dead cells from the FACS gate.