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

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

Research output: Contribution to journalArticle

375 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2427-2437
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number7
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

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T-Cell Prolymphocytic Leukemia
Immunological Synapses
B-Cell Chronic Lymphocytic Leukemia
Synapses
Pharmaceutical Preparations
T-Lymphocytes
Polymerization
Immunotherapy
Actins
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. / Ramsay, Alan G.; Johnson, Amy J.; Lee, Abigail M.; Gorgun, Gullu; Dieu, Rifca Le; Blum, William; Byrd, John C.; Gribben, John G.

In: Journal of Clinical Investigation, Vol. 118, No. 7, 01.07.2008, p. 2427-2437.

Research output: Contribution to journalArticle

Ramsay, Alan G. ; Johnson, Amy J. ; Lee, Abigail M. ; Gorgun, Gullu ; Dieu, Rifca Le ; Blum, William ; Byrd, John C. ; Gribben, John G. / Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 7. pp. 2427-2437.
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