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.
View: Text | PDF
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

×

Figure 6

Treatment of patient and Eμ-TCL1 mouse cells with lenalidomide significantly enhances immunological synapse formation.

Options: View larger image (or click on image) Download as PowerPoint
CLL T cells have reduced activation and effector function. (A) Healthy C...
Autologous T cell–sAg–pulsed CLL B cell conjugates from untreated (UT) or lenalidomide-treated (Lenalid.) CLL patient (A) or Eμ-TCL1 mouse cells (B) were selected at random for imaging and scored for accumulation of F-actin (red) at the immune synapse. As controls (healthy), autologous age-matched healthy donor or wild-type mice cells were used. Data are the mean ± SD from 3 independent experiments, with 50 conjugates analyzed per experiment. The confocal images shown are CD4+ human T cells. (C) Autologous T cell–sAg–pulsed CLL B cell conjugates from untreated CLL or lenalidomide-treated Eμ-TCL1 mouse cells were scored by visual counting using a confocal microscope. As controls, age-matched wild-type mice cells were used. Data are the mean ± SD from 3 independent experiments, with 50 random T cells analyzed per experiment. (D) Autologous T cell–sAg–pulsed CLL B cell (blue) conjugates from untreated or lenalidomide-treated patient CLL B and CLL T cells were stained for phosphotyrosine (green) and F-actin (red) using immunofluorescence and confocal microscopy. Images shown are representative of evaluation of 150 conjugates from 3 independent experiments. Arrows indicate protein localization at the T cell–APC synapse site. (E) Autologous cytotoxicity of CLL B cells was compared between untreated and lenalidomide-treated patient CLL B and CLL CD8+ T cells. Killing was assessed at the effector/target ratios shown. Data are mean ± SD from 6 independent CLL patient experiments. Autologous healthy donor cells were used as controls (with or without sAg-pulsed B cells). Original magnification, ×63.