Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling

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Abstract
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.