Natural killer (NK)-cell function and antileukemic activity of a large population of CD3+/CD8+ T cells expressing NK receptors for major histocompatibility complex class I after "three-loci" HLA-incompatible bone marrow transplantation.
We have shown that addition of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to the marrow inoculum allows engraftment of T-cell depleted, "three loci" HLA-incompatible marrow transplants for acute leukemia. The event-free survival of patients at high risk for potential of this transplant. Tumor-cell lysis by natural killer (NK) cells is regulated by inhibitory receptors for specific HLA class I alleles. Here, we report the postgrafting emergence of a large, donor-type CD3+/CD8+ T-cell receptor (TcR)-alpha beta+ cell population, barely detectable in normal subjects, that expresses 58 kD, "p58," NK receptors for HLA-C locus alleles. Analysis of > 900 clones revealed that 40% to 80% of these T cells exhibit NK-like function, i.e., they lysed class I- targets and were functionally blocked by class I alleles on target cells. Monoclonal antibody-mediated blocking of class I recognition by these cells induced lysis of HLA-protected, autologous targets. The class I-mediated inhibitory signaling through the NK receptors also blocked TcR/CD3-triggered cytotoxicity of these cells, indicating that their antigen-specific responses may be impaired. However, the NK-like function of these cells allows them to discriminate normal cells, protected from lysis, from leukemic cells that were lysed and may be targets for a graft-versus-leukemia effect.
Albi
N
N
Division of Hematology and Clinical Immunology, University of Perugia, Italy.
Ruggeri
L
L
Aversa
F
F
Merigiola
C
C
Tosti
A
A
Tognellini
R
R
Grossi
C E
CE
Martelli
M F
MF
Velardi
A
A
D000208:Acute Disease; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017252:CD3 Complex; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D011971:Receptors, Immunologic / Q000276:immunology*
D017252:CD3 Complex; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D011971:Receptors, Immunologic