TY - JOUR
T1 - Resistance to activation-induced cell death and bystander cytotoxicity via the Fas/Fas ligand pathway are implicated in the pathogenesis of cutaneous T cell lymphomas
AU - Ni, Xiao
AU - Zhang, Chunlei
AU - Talpur, Rakhashandra
AU - Duvic, Madeleine
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grants (R21-CA74117 and K24-CA 86815), Sherry Anderson Cutaneous T Cell Lymphoma Patient Research and Education Fund, and Dermatology Foundation Research Grant (GCJ7001Z). This paper was presented in part at the Society for Investigative Dermatology Meeting, May 15–18, 2002, Los Angles, CA. We thank Karen Ramirez and Wendy Schober for expert technical assistance in flow cytometry analysis, and Randall Evans, PhD for confocal microscopic analysis (NIH grant #5P30CA016672-29, Houston, TX). Thanks are also due to Hongbing Shen, PhD and Ying Yang, MS for statistical analysis (Houston, TX), to Tinhofer, PhD, for useful suggestions for cytotoxicity experiment (Innsbruck, Austria), to Francois Martin, MD for helpful discussion (Dijon, France), and to Dorothy Lewis, PhD for critical reading (Houston, TX).
PY - 2005/4
Y1 - 2005/4
N2 - By engaging Fas, Fas ligand (FasL) on activated T lymphocytes induces activation-induced cell death (AICD), and also triggers apoptosis of target cells during immune downregulation. We previously showed that within cutaneous T cell lymphoma (CTCL) lesions, malignant CD4+ T cells expressing FasL accumulated, and were inversely distributed with CD8+ T cells. We thus determined the responses of human CTCL cells to AICD and their cytotoxic to Fas+ target T cells in vitro. CTCL cells expressing Fas were resistant to AICD following activation by CD3 monoclonal antibody (mAb) whereas still undergoing apoptosis if Fas was ligated to Fas mAb. CTCL cell lines, as well as Sézary Syndrome patients' peripheral blood lymphocytes, exhibited ratio-dependent cytotoxicity to Fas+ Jurkat cells. The kinetic study showed that FasL surface expression was absent before activation, and its expression was low and/or delayed after activation. We therefore hypothesize that CTCL cells express functional FasL possibly contributing to bystander cytotoxicity within tumor infiltrates. In addition, decreased and/or delayed FasL surface expression following activation may in part contribute to their resistance to AICD. Both bystander cytotoxicity and resistance to AICD are likely to contribute to the loss of cytotoxic anti-tumor CD8+ T cells as well as the accumulation of malignant T cells in CTCL.
AB - By engaging Fas, Fas ligand (FasL) on activated T lymphocytes induces activation-induced cell death (AICD), and also triggers apoptosis of target cells during immune downregulation. We previously showed that within cutaneous T cell lymphoma (CTCL) lesions, malignant CD4+ T cells expressing FasL accumulated, and were inversely distributed with CD8+ T cells. We thus determined the responses of human CTCL cells to AICD and their cytotoxic to Fas+ target T cells in vitro. CTCL cells expressing Fas were resistant to AICD following activation by CD3 monoclonal antibody (mAb) whereas still undergoing apoptosis if Fas was ligated to Fas mAb. CTCL cell lines, as well as Sézary Syndrome patients' peripheral blood lymphocytes, exhibited ratio-dependent cytotoxicity to Fas+ Jurkat cells. The kinetic study showed that FasL surface expression was absent before activation, and its expression was low and/or delayed after activation. We therefore hypothesize that CTCL cells express functional FasL possibly contributing to bystander cytotoxicity within tumor infiltrates. In addition, decreased and/or delayed FasL surface expression following activation may in part contribute to their resistance to AICD. Both bystander cytotoxicity and resistance to AICD are likely to contribute to the loss of cytotoxic anti-tumor CD8+ T cells as well as the accumulation of malignant T cells in CTCL.
KW - Activation-induced cell death
KW - Apoptosis
KW - Cutaneous T cell lymphoma
KW - Fas
KW - Fas ligand
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U2 - 10.1111/j.0022-202X.2005.23657.x
DO - 10.1111/j.0022-202X.2005.23657.x
M3 - Article
C2 - 15816832
AN - SCOPUS:16844371989
SN - 0022-202X
VL - 124
SP - 741
EP - 750
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 4
ER -