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 1

CLL patients have impaired T cell immune synapse formation.

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CLL patients have impaired T cell immune synapse formation. (A) T cell c...
(A) T cell conjugates formed between T cells from CLL patients or age-matched healthy donors and sAg-pulsed autologous CLL B cells or healthy B cells, respectively, were scored by visual counting using a confocal microscope. Each data set shows the mean ± SD from 6 independent experiments, with 50 random T cells analyzed per experiment. (B) Autologous conjugate experiments were performed as in A, comparing CLL patients with low (less than 20 mm3) absolute wbc versus high wbc (20 mm3 or more) with age-matched healthy donor cell conjugates. Each data set shows the mean ± SD from 3 independent experiments, with 50 random T cells analyzed per experiment. (C) T cells from CLL patients or age-matched healthy donors were allowed to conjugate with autologous CLL cells or healthy B cells, respectively, with or without sAg (blue, CMAC dyed). Conjugates were then fixed and stained with rhodamine phalloidin to detect F-actin (red). Note the lack of F-actin enrichment at the synapse site in T cells from CLL even in the presence of sAg-pulsed CLL cells. Original magnification, ×63. (D) Conjugates were selected at random for imaging and were scored for accumulation of F-actin at the immune synapse. Each data set shows the mean ± SD from 9 independent patient experiments, with 50 conjugates analyzed per experiment.