Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells
Güllü Görgün, Tobias A.W. Holderried, David Zahrieh, Donna Neuberg, John G. Gribben
Güllü Görgün, Tobias A.W. Holderried, David Zahrieh, Donna Neuberg, John G. Gribben
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Research Article Immunology

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

Abstract

To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity.

Authors

Güllü Görgün, Tobias A.W. Holderried, David Zahrieh, Donna Neuberg, John G. Gribben

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Figure 4

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Impact of T cell–cancer cell contact on healthy T cells. Highly purified...
Impact of T cell–cancer cell contact on healthy T cells. Highly purified T cells from healthy donors were cocultured with B cells from CLL patients or from their HLA-matched healthy donors at a 2:1 (T/B cell) ratio for 48 hours. (A) Decrease in 65-kDa NF-κB and increase in 41-kDa Arp3 in healthy CD4 cells after contact with allogeneic CLL cells (C1 and C2) and healthy B cells (H). (B) Decrease in 190-kDa Rho-GAP and increase in 41-kDa Arp3 in healthy CD8 cells after contact with CLL cells (C1 and C2) and healthy allogeneic B cells (H). (C) Impact of CLL cell contact on cytoskeletal protein expression in allogeneic healthy T cells, confirmed by ICAM1 or LFA1 blocking. Highly purified CD4 or CD8 cells from healthy donors were cocultured with B cells from CLL patients (C1 and C2) or healthy donors (H) with or without blockade of the LFA1 or ICAM1 interaction. Expression of 190-kDa Rho-GAP in healthy CD8 cells was increased after blockade of the ICAM1 during CLL cell–T cell contact, and expression of 41-kDa Arp3 in CD4 T cells and 25-kDa CDC42 in healthy CD8 cells was decreased after blockade of the LFA1 or ICAM1. –, protein expression in nonblocked cells; +, protein expression in blocked cells. Protein expressions were normalized by GAPDH expression level and are shown as protein bands and densitometric intensity of each band. The figure is representative of 3 different experiments performed with 6 different patients with CLL and 6 different healthy donors showing a similar pattern (P < 0.05).