Adhesion molecule-mediated signals regulate major histocompatibility complex-unrestricted and CD3/T cell receptor-triggered cytotoxicity (original) (raw)
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European Journal of Immunology, 1998
T cell activation is known to depend not only on efficient antigen recognition and subsequent signaling through TCR, but also on interactions involving multiple adhesion and accessory molecules such as CD28/B7, LFA-1/ICAM-1 and LFA-3/CD2. The present study dissects the role of LFA-3/CD2 interactions in the activation of melanoma-specific CD8 + T cell clones. To this end we analyzed the influence of LFA-3 density on melanoma cells on lysis and cytokine production (TNF, IL-2, IFN-+ ) by T cells following activation by various amounts of antigenic peptides. Our results indicate that increasing LFA-3 density on melanoma cells variably affects their lysis susceptibility, but systematically and considerably enhances cytokine production by melanoma-specific cytotoxic T lymphocyte (CTL) clones. At any stimulatory antigen density, LFA-3 increased the fraction of responding cells and/or cytokine amounts produced by individual cells, without affecting TCR down-regulation. These results show that CD2 engagement increases cytokine gene activation essentially by providing to T cells a TCR-independent co-activation signal. From a practical point of view, our data demonstrate that the level of LFA-3 expressed on tumors critically affects cytokine production by specific CTL and thus the efficiency of specific immune reactions mediated by these cells.
European Journal of Immunology, 1988
Although intercellular adhesion molecule-1 (ICAM-1) has been implicated as a ligand in some LFA-1-dependent adhesion, its importance to T cell function has not been established. The present studies investigate the importance of ICAM-1 for human cytotoxic T lymphocytes (CTL), both in their formation of antigen-independent conjugates (AIC) and in their lysis of targets. Analysis of monoclonal antibody (mAb) inhibition of AIC formation indicate that ICAM-1 mAb 1 blocks (a) AIC formation with some but not all targets; (b)the LFA-1 pathway but not the CD2LFA-3 pathway of adhesion; (c) by binding to the target cell, not the T cell. In studies of cell-mediated lysis (CML) ICAM-1 mAb inhibited lysis of some targets, such as U-937, that use ICAM-1 predominantly in AIC formation; CML on some other targets is not inhibited by ICAM-1 mAb. These data indicate that ICAM-1 is a ligand for AIC formation, antigen-specific CTL recognition and cytolysis of particular target cells. The data also indicate that ICAM-1 is not used in LFA-1-dependent CTL interactions with all kinds of target cells, suggesting the existence of alternative ligands for LFA-1.
Cellular Immunology, 1990
We have shown that intercellular adhesion molecule-l (ICAM-1) (CD54) positive cells are mainly responsible for the natural cytotoxic function of human blood lymphocytes. The evidences were the inhibition of cytotoxicity by anti-ICAM-(LB-2) monoclonal antibodies (mAb) and the loss of lytic activity after removal of the ICAM-I + cells. In addition, the cytotoxic potential of the separated ICAM-I-lymphocyte population after activation appeared in parallel with the expression of this molecule. The ICAM-I+ lymphocytes lysed both LFA-1 (CD1 la/CD1 8 or Leu-CAMa) positive and negative cell lines, and pretreatment of the effecters with the LB-2 mAb also inhibited the lysis of LFA-I-targets. The results point to a yet unrecognized role of ICAM-I on the lymphocytes. Kinetics experiments suggested that pretreatment of lymphocytes with (Y-ICAM-I (LB-2) mAb did not inhibit the promptly established lytic interactions but influenced later events, recycling and/or recruitment of effecters. It is possible that the cytotoxic potential is regulated by contacts between the members of the lymphocyte population and that these events occur via their ICAM-I and LFA-I. Exposure of lymphocytes to NK-sensitive targets for 16 hr elevated their cytotoxic potential. The function of activated lymphocytes was not inhibited by the LB-2 mAb.
European Journal of Immunology, 1993
It is well established that adhesion molecules are required for interaction between cytotoxic T lymphocytes (CTL) and target cells. Two adhesion pathways, CD2/LFA-3 and LFA-l/ICAM-1 can support cytotoxicity by allospecific CD8+ CTL. In this study, it was investigated whether these adhesion pathways can be utilized independently by influenza virus-specific HLA-A2-restricted CTL clones. It was furthermore examined whether the CD28/B7 pathway can augment virus-specific CTL activity. To this end, seven CD8+ CTL clones were established that were specific for a peptide encompassing positions 59 to 68 (p[59-68]) of the influenza virus matrix protein. These seven clones apparently originated from different precursors, as they utilized different Vα and Vβ or Jα gene segments. Six of seven clones were able to lyse mouse L cells co-transfected with HLA-A2 and either LFA-3 (LA2/LFA-3) or ICAM-1 (LA2/ICAM-1) in the presence of p[59-68] but did not lyse Lcells that expressed only HLA-A2 and peptide. Three of the most cytotoxic clones were selected for further analysis. The cytotoxicity of the clones against LA2/LFA-3 cells was blocked by anti-LFA-3 and anti-CD2 monoclonal antibodies (mAb), while these antibodies did not affect cytotoxicity against LA2/ICAM-1 cells. Likewise, the activity against LA2/ICAM-1 was blocked only by anti-LFA-1 and ICAM-1 mAb. These clones were unable to lyse Lcells co-transfected with HLA-A2 and B7, the counter structure of CD28, despite the fact that these clones expressed CD28. These data indicate that CD8+ virus-specific CTL can utilize either the CD2/LFA-3 or the LFA-l/ICAM-1 adhesion pathway. The CD28/B7 pathway seems not to be required for cytotoxicity mediated by activated virus-specific CTL.
Cellular Immunology, 1989
Activation of human-purified T cells can be mediated by pairwise combinations of monoclonal antibodies directed against T 11.1 and Tl 1.2 epitopes on the CD2 molecule. Monoclonal antibodies (mAbs) reactive with either the a and /3 chains of the lymphocyte-function-associated antigen-1 (LFA-1) molecule or one of its ligands, intercellular adhesion molecule-1 (ICAM-1 ), were found to accelerate anti-CD2-induced proliferation. This effect was seen on thymocytes and resting or preactivated T cells (phytohemagglutinin blasts and alloproliferative T cell clones) and could be observed, following the introduction of anti-LFA-1 or -ICAM-l mAbs, up to 50 hr after the CD2 stimulatory signal. This effect was equally abrogated by 55 kDa anti-interleukin-2 (IL-2) receptor mAb, but neither the expression of IL-2 receptor nor the production of IL-2 was modified. The effects of anti-LFA-1 or anti-ICAM-1 on T cell activation through the CD2 pathway were therefore opposite to those observed in the CD3 pathway, where both mAbs strongly delayed T cell proliferation. 0 1989 Academic PXS, Inc.
Cancer Immunology Immunotherapy, 1990
In a group of 30 human tumors, comprising 12 lung, 14 ovarian, 2 breast carcinomas, 1 hypernephroma and 1 mid-gut carcinoid, the expression of major histocompatibility complex (MHC) class I molecules and the intercellular adhesion molecule 1 (ICAM-1, CD54) was found to vary independently. Some tumors expressed both or neither of these molecules. Among 9/13 ICAM-1 + tumors, in which >50% cells reacted with the anti-ICAM-1 monoclonal antibody (mAb) (LB-2), the class I antigen was also detected on >50% of the cells. Only 2 ICAM-1 + tumors were class-I-. In 5/17 cases the tumors were MHC-class-I + and ICAM-1-. Lymphocytes collected f rom the blood or from the tumor site were assayed for recognition on the tumor cells in the auto-tumor cytotoxicity test and in mixed lymphocyte tumor cell culture (MLTC). Positive results were obtained only with the MHC-class-I+/ICAM-1 + tumors. In vitro treatment of the tumor cell suspensions with interferon 5, and tumor necrosis factor a (TNFcQ induced or enhanced the ICAM-1 and/or class I antigen expression in 8/12 cases. Of the tumor samples treated, 8/9 aquired stimulatory capacity and 3/10 became susceptible to lysis by the lymphocytes. In 6/6 MLTC performed with the cytokine-treated tumor cells, cytotoxicity against the autologous tumor was generated. Three of these MLTC lymphocytes also lysed the untreated targets, mAb directed to class I antigens or to ICAM-1 inhibited both the stimulation by and the lysis of tumor cells when confronted with fresh lymphocytes. The eytotoxicity generated in the MLTC was also inhibited. If, however, the cytotoxic function was induced in MLTC containing interleukin-2 (5 U/tal), inhibition was obtained only by pretreatment of the targets with mAb against ICAM-1. The results show thus (a) that the lymphocytes react in vitro with tumor cells only if these express both MHC class I molecules and ICAM-1; (b) that expression of these molecules can be induced by interferon « and TNFa; (c) that cytotoxic effectors generated in the MLTC with cytokine-treated tumors can also act on the untreated tumor cells. The requirement of the two surface moieties for the interaction with lymphocytes was also substantiated by blockade with relevant mAb.
The Journal of Immunology, 1983
Human lymphocyte function-associated antigen (LFA)-7, a heterodimeric lymphocyte surface glycoprotein of 177,000 and 95,000 relative molecular weight has been implicated to function in the cytotoxic T lymphocyte (CTL) effector mechanism. Seven mouse hybridoma lines producing monoclonal antibodies (MAb) reactive with this structure were studied. Three unique and 3 partially overlapping epitopes on human LFA-1 were defined by competitive cross inhibition binding assays using biosynthet-'ically labeled anti-LFA-1 MAb. In contrast, of five rat antimouse LFA-1 MAb, all five recognized a common or shared epitope. An HLA-67 specific human CTL line expressed 1.1 x lo5 LFA-1 sites per cell with a direct saturation binding assay. Human CTL expressed two to four times more LFA-1 than peripheral blood lymphocytes or B and T lymphoblastoid cell lines. Titration of each of the anti-LFA-1 MAb in a 5'chromium release cytolytic assay revealed quantitative differences in the ability of the different anti-LFA-1 MAb to block cytolysis indicating distinct functional and antigenic epitopes exist on the human LFA-1 molecule. Anti-LFA-1 MAb reversibly inhibited the CTL reaction by slowing the initial rate of cytolysis. These results suggest anti-LFA-1 MAb inhibit CTL function by specific blockade of a functionally relevant molecule.
International Journal of Cancer, 1995
Adoptive immunotherapy against cancer has met with varying degrees of success, the reasons for which remain unclear. The present study characterizes factors that regulate successful immunotherapy of mice bearing a syngeneic T-cell lymphoma, designated LSA, using a tumor-specific cytotoxic T lymphocyte (CTL) clone, PE-9. Adoptive transfer of PE-9 cells afforded significant protection in normal but not in nude mice against LSA tumor. However, the PE-9 cells could protect the nude mice when injected along with normal CD4+ T cells. Administration of IL-2 along with PE-9 cells failed to enhance tumor immunotherapy. IL-2 therapy was toxic inasmuch as injection of the CTL clone PE-9 + IL-2, but not PE-9 or IL-2 alone, for 5 days into irradiated mice caused vascular leak syndrome (VLS). PE-9 cells cultured with high doses of rlL-2 in vitro also caused TCR-independent and MHC-unrestricted lysis of SV40-transformed endothelial cells. Furthermore, PE-9 cells cultured in vitro for 24-96 hr with 11-2 exhibited cycling pattern of tumorspecific cytotoxicity with maximum cytotoxicity demonstrable at 48 hr and virtually no cytolytic activity at 96 hr of culture or thereafter. The loss of cytotoxicity correlated with downregulation of several adhesion molecule expressions on PE-9 cells, particularly the aS-TCR, as well as the mRNA for TNF-a, fibroblast cell line also of H-2k origin (SVC3H), kindly provided by L. Gooding (Atlanta, GA) were maintained in culture 3To whom correspondence should be addressed,