Analysis of the activating receptors and cytolytic function of human natural killer cells undergoing in vivo differentiation after allogeneic bone marrow transplantation

Abstract

Patients undergoing allogeneic bone marrow transplantation offer a unique system to analyze NK cell development in vivo. We analyzed NK cells from 23 such patients to assess the acquisition of activating receptors. Four patients displayed an immature NK cell surface phenotype at engraftment, as their cells were CD16 -KIR -and NKG2D -but expressed low levels of NKp46, NKp30, 2B4 and NKG2A. These NK cells had particularly low cytolytic activity against the HLA-class-I -melanoma F01 cell line and the 721-221 EBV-infected B cell line. Moreover, cytoxicity was inhibited upon mAb-mediated crosslinking of 2B4. Analysis of NK cells at day 30 after bone marrow transplantation revealed the occurrence of both phenotypic and functional maturation. These data are in agreement with a previous in vitro study showing that immature NK cell precursors express CD16, NKG2D and KIR only at a late stage of differentiation and also express inhibitory 2B4. Our present study allows a better understanding of the NK cell differentiation in vivo.

CD56dimCD16neg cells are responsible for natural cytotoxicity against tumor targets

“…Immature NK cell precursors (eg in peripheral blood after allogeneic bone marrow transplantation and in umbilical cord blood) are predominantly CD56 pos /CD16 neg , during NK cell differentiation CD16 expression increases with impact on NK cell functionality. [29][30][31][32][33][34] In all tests, no considerable expression of CD107a was detected on CD56 dim /CD16 pos cells, indicating that these cells do not degranulate in response to NK-sensitive leukemia targets and do not exhibit direct cytotoxicity. Since CD16 surface expression is crucial for antibody-dependent cellular cytotoxicity, it is reasonable that the CD56 dim /CD16 pos cells are the major effector cells mediating this type of cytotoxic response.…”

CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A

“…22 In the first months after SCT, NK cell subsets were shown to be characterized by a high frequency of CD94:NKG2A expression and low expression of KIR. [19][20][21] This suggests that at early stages after SCT, the function of NK cells is primarily regulated through the interaction of CD94:NKG2 heterodimeric complexes with HLA-E molecules.…”

Early evaluation of natural killer activity in post-transplant acute myeloid leukemia patients

“…[18][19][20] The graft-versus-leukemia (GvL) 21 effect mediated by donor-derived immune effectors early after hematopoietic stem cell transplantation (HSCT) may eradicate residual tumor cells and may be crucial in preventing disease relapse. Donor-derived NK cells typically undergo differentiation within 30 days 22 and might thus participate in an early GvL effect. In acute myeloid leukemia (AML), the contribution of NK cells to GvL has been strikingly shown in KIR-HLA-C mismatched haploidentical HSCT, where donor-derived NK alloreactive clones could eradicate residual blasts.…”