Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug
Alan G. Ramsay, … , John C. Byrd, John G. Gribben
Alan G. Ramsay, … , John C. Byrd, John G. Gribben
Published June 12, 2008
Citation Information: J Clin Invest. 2008;118(7):2427-2437. https://doi.org/10.1172/JCI35017.
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Research Article Hematology

Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug

Abstract

Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.

Authors

Alan G. Ramsay, Amy J. Johnson, Abigail M. Lee, Güllü Gorgün, Rifca Le Dieu, William Blum, John C. Byrd, John G. Gribben

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Figure 5

CLL T cells have reduced activation and effector function.

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Treatment of patient and Eμ-TCL1 mouse cells with lenalidomide significa...
(A) Healthy CD8+ and CD4+ T cells were cocultured for 48 h as described in Figure 4. T cell conjugates formed during 5 min were fixed, permeabilized, and stained with anti-phosphotyrosine Ab (green) and rhodamine phalloidin (red). Quantitative image analysis (relative recruitment index [RRI]) of phosphotyrosine accumulation at the immunological synapse is shown, representative of evaluation of 150 conjugates from 3 independent experiments (50 conjugates analyzed per experiment), with the mean value shown as a black bar. Original magnification, ×63. (B) Healthy CD3+ T cells were first cocultured in direct contact with allogeneic healthy B cells or 3 different CLL B cells (CLL 1-3) with the addition of anti–ICAM-1 monoclonal antibody or isotype control IgG, and then were used in secondary MLRs with third-party allogeneic PBMCs as stimulators. [3H]-thymidine incorporation was assessed for the last 16 h of a 3-d culture. The stimulation index was calculated as cpm of T cells with stimulator cells/cpm of T cells alone. Results are the mean stimulation index ± SD from 5 independent healthy donor CD3+ T cells. IL-2 was assessed by ELISA, and values represent the mean ± SD from 5 independent healthy donor CD3+ T cells tested. (C) HLA-A*0201–expressing CD8+ cells were stimulated in vitro with DCs pulsed with immunoglobulin heavy chain–derived (IgVH-derived) peptide TLYLQMNSL weekly for 4 wk, and killing of peptide-pulsed H2 cells was assessed at the effector/target ratios shown. The results are the mean ± SD from 6 independent CLL patient and healthy donor experiments.