Beta1 integrin triggering affects leukemic cell line sensitivity to natural killer cells.
The role of beta1 (CD29) integrins in natural killer (NK) cell-target cell conjugation and cytotoxicity has not been clearly established. Ligation of beta1 integrins in NK cells can modulate the lytic capacity in both a positive and a negative manner; however, the contribution of the beta1 integrins present on target cells remains to be evaluated. Here, we analyzed the effect of beta1 integrins expressed by potential tumor target cells on conjugation and cytotoxicity. Using normalized flow cytometry binding assays, we demonstrated that the pretreatment of MOLT-4, K562, U-937 and HL-60 human leukemia target cell lines with selected anti-beta1 monoclonal antibodies (mAb) increased conjugation to human NK cell line NKL as well as to purified NK cells. Only mAb recognizing residues 207-218 of the beta1 subunit and functionally involved in the induction of homotypic adhesion (functional epitope A1) increased conjugation of all the target cells. Moreover, mAb to adhesion molecules different from beta1 but also inducers of homotypic adhesion of the target cells, i.e. CD43 and CD50 (ICAM-3), failed to increase conjugation to NKL cells. Cytotoxicity assays demonstrated that lysis of NK-sensitive target cells (MOLT-4) also increased after pretreatment with anti-beta1 epitope A1 mAb. Importantly, pretreatment of NK-resistant target cells (U-937 and HL-60) with anti-beta1 mAb was not able to outweigh the cytotoxic inhibitory mechanisms controlled by HLA class I molecules. However, simultaneous masking of HLA class I molecules with mAb and pretreatment with anti-beta1 mAb rendered NK-resistant cells susceptible to lysis, as predicted by the missing self hypothesis. Triggering of tumor target cells through beta1 integrins may thus play a role in conjugation to NK cells as well as in co-stimulation of cell-mediated cytotoxicity.
Rubio
Gonzalo
G
Division of Immunology, Miguel Hernandez University, 03550 San Juan de Alicante, Spain.
Ferez
Xabier
X
Mora
Ana
A
Galvez
Jesus
J
Chicano
Antonio
A
Garcia-Peñarrubia
Pilar
P
D000911:Antibodies, Monoclonal / Q000378:metabolism; D002449:Cell Aggregation; D002460:Cell Line; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D000939:Epitopes; D019012:Integrin beta1; D008024:Ligands