Immunobiology - TCR gamma delta cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells

Cytotoxic T lymphocytes (CTL) are thought to play an important role in the graft-versus-leukemia (GVL) response. Unfortunately, GVL reactivity is ofte n associated with life-threatening graft-versus-host disease (GVHD), Charac terization of CTL that selectively attack leukemic cells but not normal cel ls may lead to the development of adjuvant immunotherapy that separates GVL from GVHD, Here, we describe TCP gamma delta (V beta9/V delta1) CTL, isola ted from the peripheral blood of an AML patient after stem cell transplanta tion (SCT), that very efficiently lysed freshly isolated acute myeloid leuk emia (AML) cells and AML cell lines. Interestingly, HLA-matched non-maligna nt hematopoietic cells were not killed. We revealed that the killer cell-in hibitory receptor (KIR) p58.2 (CD158b) specific for group 2 HLA-C molecules negatively regulates the cytotoxic effector function displayed by these TC R gamma delta CTL, First, an antibody against HLA-C enhances lysis of nonma lignant cells. Secondly, stable transfection of HLA-Cw*0304 into the class I-negative cell line 721.221 inhibited lysis, Finally, engagement of p58.2 by antibodies immobilized on Fc gammaR-expressing murine P815 cells inhibit s CD3- and TCR gamma delta -directed lysis, Compared to non-malignant hemat opoietic cells, AML cells express much lower levels of MHC class I molecule s making them susceptible to lysis by p58.2(+) TCR gamma delta CTL, Such KI R-regulated CTL reactivity may have a role in the GVL response without affe cting normal tissues of the host and leading to GVHD.