ICAM- melanoma cells are relatively resistant to CD3-mediated T-cell lysis.
The primary activation pathway of T cells is via the T-cell receptor (TCR)/CD3 complex, which is functionally interrelated with various accessory molecules. We examined the contribution of the lymphocyte-function-associated antigen-I/intercellular adhesion molecule 1 (LFA-1/ICAM-1) interaction to CD3/TCR-mediated lysis by cytotoxic T lymphocytes (CTL). We used ICAM-I-or+ tumor cell lines as target cells and anti-CD3- or anti-LFA-1 containing hetero-cross-linked monoclonal antibody (MAb) to bridge CTL and target cells and simultaneously to activate CTL. The ICAM-1- melanoma-derived cell line IgR39 was relatively resistant to CD3-mediated lysis by both TCR alpha beta + and TCR gamma delta + CTL, when compared with ICAM-1+ cell lines. Induction of ICAM-1 on the membrane of IgR39 cells by tumor necrosis factor (TNF) rendered these cells more susceptible to CD3-mediated lysis. Anti-ICAM-1 MAb inhibited this TNF-enhanced susceptibility to lysis, directly demonstrating that the induction of ICAM-1 was critical in the TNF-induced increase in susceptibility to lysis of IgR39 cells. CTL formed less efficient conjugates with the ICAM-1- cells as compared to ICAM-1+ cells. Both spontaneous and CD3-induced conjugate formation as well as CD3-mediated lysis of ICAM-1- tumor cells by CTL were enhanced by the addition of anti-LFA-1 containing hetero-cross-linked MAb, thereby mimicking the LFA-1/ICAM-1 interaction between CTL and target cells. Soluble anti-CD18 MAb inhibited CD3-mediated lysis of ICAM-1- target cells by CTL without affecting their conjugate formation. Anti-LFA-1 MAb added after conjugate formation still inhibited lysis of both ICAM-1+or- tumor cells. Taken together, these findings suggest that the LFA-1/ICAM-1 interaction co-activates CD3/TCR-mediated lysis by CTL through both an enhanced CTL-target cell binding and the delivery of post-conjugate costimulatory signals.
Braakman
E
E
Dept. of Immunology, Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Goedegebuure
P S
PS
Vreugdenhil
R J
RJ
Segal
D M
DM
Shaw
S
S
Bolhuis
R L
RL
D000911:Antibodies, Monoclonal / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016028:Receptors, Leukocyte-Adhesion / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D016028:Receptors, Leukocyte-Adhesion; D018799:Intercellular Adhesion Molecule-1