Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling.
Extensive phenotype analysis of cutaneous T-cell lymphoma (CTCL) malignant cell lines revealed surface expression of receptors usually not detected on normal circulating CD4(+)CD45RO(+) lymphocytes. We previously found that CTCL malignant cells express the killer cell immunoglobulinlike receptor (KIR) KIR3DL2/CD158k, whereas they fail to express the other KIRs. In the present study, we report for the first time that the CD85j/immunoglobulin (Ig)-like transcript 2 (ILT2) receptor is found on Sézary cell lines and on circulating Sézary malignant CD4(+) cells, while it is hardly detectable on circulating CD4(+) lymphocytes from healthy individuals. We demonstrate that ILT2 is functional on CTCL cells, as its triggering leads to the recruitment of Src homology 2 domain-containing tyrosine phosphatase (SHP-1) and to the specific inhibition of CTCL malignant cell proliferation induced by CD3/T-cell receptor (TCR) stimulation. Interestingly, we found that separated CD4(+)ILT2(+) circulating malignant Sézary cells are less susceptible to anti-CD3 monoclonal antibody (mAb)-induced cell death than autologous CD4(+)ILT2(-) lymphocytes. Therefore, the resistance to apoptosis of Sézary cells may result from distinct mechanisms including cytokine-induced high levels of bcl-2 and specific expression of inhibitory receptors involved in lymphocyte survival.
INSERM 448 and Dermatology Department, Faculté de Médecine de Créteil, Créteil, France.
Maria
M
Nikolova
Philippe
P
Musette
Martine
M
Bagot
Laurence
L
Boumsell
Armand
A
Bensussan
D015703:Antigens, CD / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008213:Lymphocyte Activation; D016410:Lymphoma, T-Cell, Cutaneous / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000378:metabolism; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D054347:Receptors, KIR3DL2; D012751:Sezary Syndrome / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*
D015703:Antigens, CD; D017252:CD3 Complex; D047908:Intracellular Signaling Peptides and Proteins; C515077:KIR2DL2 protein, human; C515084:KIR3DL2 protein, human; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D054347:Receptors, KIR3DL2; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases