Lymphocyte leukocyte function-associated antigen 1 interacting with target cell intercellular adhesion molecule 1 co-activates cytolysis triggered via CD16 or the receptor involved in major histocompatibility antigen-unrestricted lysis

The binding of leukocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) to its natural target ligand, intercellular adhesion molecule 1 (ICAM-1) (CD54), is an important step in lymphocyte adhesion to cells and its subsequent activation. We studied whether LFA-1 - ICAM-1 interactions affect tumor cell suceptibility to MHC-unrestricted lysis by TCR-CD3-CD16⁺ natural killer (NK) and TCRγδ⁺CD3⁺CD16^+/- lymphocytes. Moreover, tumor target cell susceptibility to anti-CD16 mAb-triggered lysis by TCR- NK cells was investigated. Therefore, ICAM-1⁺ or ICAM-1^- tumor cell lines were used as target cells. Two melanoma-derived cell lines expressing little or no ICAM-1 were relatively resistant to MHC-unrestricted lysis as well as anti-CD16 mAb-triggered lysis by fresh or cloned TCR^- NK cells. The ICAM-1^- melanoma cell line was also relatively resistant to MHC-unrestricted lysis by TCR^+/+ clones. Tumor necrosis factor (TNF) induced ICAM-1 expression on ICAM-1^- tumor cells, and simultaneously increased target cell susceptibility to MHC-unrestricted as well as to anti-CD16 mAb-triggered lysis. This enhanced level of lysis was inhibited by anti-ICAM-1 mAb. Our data demonstrate that LFA-1-ICAM-1 interactions increase MHC-unrestricted or CD16-mediated cytolysis of tumor cells. Anti-CD18 (LFA-1β) mAb inhibited MHC-unrestricted lysis of ICAM-1⁺ and ICAM-1^- tumor cells. However, anti-CD18 mAb only blocked formation of lymphocyte-target cell conjugates with ICAM-1⁺ but not with ICAM-1^- target cells. These results suggest that LFA-1 can mediate positive as well as negative signals. Our data also show that LFA-1-ICAM-1 interactions co-activate and regulate cytotoxicity triggered via the receptor structure(s) involved in MHC-unrestricted lysis as well as via CD16.