Natural killer cell acceptance of H-2 mismatch bone marrow grafts in transgenic mice expressing HLA-Cw3 specific killer cell inhibitory receptor (CD158b)

Abstract

Natural killer (NK) cells express killer cell inhibitory receptors (KIRs) for major histocompatibility complex class I molecules. Engagement of these surface receptors inhibits NK cell cytotoxic programs. KIR can also be expressed on T cell subsets, and their engagement similarly results in inhibition of effector functions initiated by the CD3͞T cell receptor complex. KIR genes belong to two distinct families: the immunoglobulin superfamily (IgSF KIRs) and dimeric C2 lectins (lectin-like KIRs). Whereas both IgSF (p58: CD158, p70, and p140) and lectin-like KIRs (CD94͞NKG2A heterodimers) have been found in human, only lectin-like KIRs (all members of the Ly-49 family) have been described in the mouse. We have generated transgenic mice expressing an IgSF KIR, CD158b (p58.2), which recognizes HLA-Cw3. Our data show that CD158b is necessary and sufficient to confer specificity to NK cells, as well as to modulate T cell activation programs in vitro. In addition, we did not detect any adaptation of CD158b cell surface expression to that of HLA class I ligands in the CD158b ؋ HLA-Cw3 double transgenic mice, in contrast to observations with Ly-49 in the mouse. Therefore, distinct strategies of selection͞calibration appear to be used by IgSF and lectin-like KIRs. Finally, the transgenic expression of CD158b KIR prevents the in vivo rejection of H-2 mismatch bone marrow grafts, which express the cognate major histocompatibility class I HLA-Cw3 allele, demonstrating for the first time the in vivo implication of human IgSF KIRs in the negative regulation of NK cell function.

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

“…Also, it has been reported that p58.2 (CD158b) + T cells increase after HLAmatched allogeneic SCT. 28 Cambiagi et al 29 showed that transgenic expression of the CD158b KIR prevents in vivo rejection of an H-2-mismatched mice bone marrow graft. Together, these data suggest that CD158b + T cells and NK cells displaying non-MHC-restricted lysis may have some role in selective anti-leukemic reactivity following SCT, while normal cells are protected from lysis thereby reducing GVHD.…”

Killer Cell Ig-Like Receptor and Leukocyte Ig-Like Receptor Transgenic Mice Exhibit Tissue- and Cell-Specific Transgene Expression

“…In vivo models would provide a system to allow such problems to be addressed. Previous work generated KIR2DL3 transgenic mice, and used them to investigate KIR function and the possible affects the ligand for this KIR, HLA-Cw3, exerts on KIR expression (32). This study showed that KIRs can be expressed without the need for the presence of their cognate human ligands, MHC class I.…”

Analysis of donor NK and T cells infused in patients undergoing MHC-matched allogeneic hematopoietic transplantation

“…Indeed, the rejection of parental bone marrow graft by a F1 hybrid can be abrogated by the transgenic expression of HLA-Cw3 and the cognate KIR (CD158b) in the parental donor and F1 recipient, respectively. 23 Along this line, the treatment of leukemia-bearing mice with F(abЈ) 2 fragments of monoclonal antibody (mAb) against Ly49C and I, as well as adoptive transfer of NK cells treated ex vivo with the same F(abЈ) 2 fragments, resulted in significant increases in mouse survival, demonstrating that blockade of inhibitory MHC class I-specific NKR enhances anti-tumor activity in vivo. 24 In both humans and mice, the presence of KIR/MHC class I incompatibility (KIR epitope incompatibility) between donors and recipients of HLA-mismatched allogeneic transplantation, ie when the donor KIR repertoire fails to recognize the HLA epitopes of the recipient, was recently demonstrated to be associated with anti-leukemic activity of donor-derived NK cell clones.…”