Lymphocyte Function-Associated Antigens: Regulation of Lymphocyte Adhesions in Vitro and Immunity in Vivo
Antibodies to most cytolytic T lymphocyte (CTL) external membrane antigens have no effect on CTL-mediated killing in the absence of complement. However, antibodies which do inhibit killing have now been identified for 7 distinct molecular sites. Antibodies to 6 of these “lymphocyte function-associated antigens” (LFAs, also called “blocking sites”) inhibit when bound to the CTL, and to the 7th, when bound to the target cell. Mouse homologs have been identified for only 4 of the 7 human LFAs. 5 (probably 6) of the blocking sites inhibit by interfering with adhesion formation between the CTL and the target cell; the exception is T3. None of the presently identified blocking sites are believed to be lethal hit structures (CTL “toxin”).
Reduction of target cell H-2 alloantigen density by pretreatment with papain reduces CTL-target functional “affinity”, and increases susceptibility to inhibition 100-fold for anti-Lyt- 2,3 and 10-fold for anti-LFA-1. This is consistent with the hypothesis that Lyt-2,3 aids in recognition of class 1 MHC antigens, perhaps by strengthening intercellular adhesion.
On the other hand, LFA-1 appears to function differently. Trypsin pretreatment of target cells has little effect on MHC antigens or CTL-target affinity, yet still increases by 10-fold susceptibility to inhibition by anti-LFA-1. This is seen in both
human and mouse CTL systems. These results suggest the existence of a non-MHC target structure which participates in the adhesion- strengthening function of LFA-1, and which is trypsin (and papain) sensitive: the “trypsin-sensitive counter blocker” (TSCB). LFA-3 may be the human TSCB.
The roles of these LFAs in intercellular adhesion extend to more general cell adhesions. Anti-LFA-1 and ainti-LFA-3 weaken the spontaneous adhesions which form between cells of the human B cell line JY. These homotypic adhesions are not initiated by immunologic recognition.
Anti-LFA-1 is more potent at prolonging allograft survival in vivo than are anti-Lyt-2,3, anti-T200, anti-Thy-1, or anti-I-A. Thus, the potent anti-adhesion properties of LFA-1 seen in vitro may lead to useful immunotherapy in the clinic.
KeywordsVortex Sarcoma Polypeptide Interferon Trypsin
Unable to display preview. Download preview PDF.
- Bernard, A., Bernstein, I., Boumsell, L., Dausset, J., Evans, R., Hansen, J., Haynes, B., Kersey, J., Knapp, W., McMichael, A., Milstein, C., Reinherz, E., Ritts, R. E., and Schlossman, S. F., 1984, Differentiation human leucocyte antigens: a proposed nomenclature. Immunol. Today, 5:158.CrossRefGoogle Scholar
- Dialynas, D. P., Quan, Z. S., Wall, K. A., Pierres, A., Quintans, J., Loken, M. R., Pierres, M., and Fitch, F. W., 1983, Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J. Immunol., 131:2445.PubMedGoogle Scholar
- Drebin, J. A., Waltenbaugh, C., Schatten, S., and Greene, M. I., 1983, Inhibition of tumor growth in hybrids by in vivo administration of monoclonal anti-I-J antibodies reactive with either parental haplotype. J. Immunol., 130:505.Google Scholar
- Gromkowski, S. H., Heagy, W. E., Sanchez-Madrid, F., Springer, T. A., and Martz, E., 1983, Blocking of CTL-mediated killing by monoclonal antibodies to LFA-1 and Lyt-2,3 I. Increased susceptibility to blocking after papain treatment of target cells. J. Immunol., 130:2546.Google Scholar
- Gromkowski, S. H., Heagy, W. H., and Martz, E., 1984a, Blocking of CTL-mediated killing by monoclonal antibodies to LFA-1 and Lyt-2,3 II. Evidence that trypsin pretreatment of target cells removes a non-H-2 molecule important in killing. Submitted for publication.Google Scholar
- Gromkowski, S. H., Krensky, A., Martz, E., and Burakoff, S. J., 1984b, Functional distinctions between the LFA-1, LFA-2, and LFA-3 membrane proteins on human CTL are revealed with trypsin pretreated target cells. J. Immunol., in press.Google Scholar
- Gromkowski, S. H., Krensky, A. M., Burakoff, S. J., and Martz, E., 1984c, LFA-1 and LFA-3 membrane molecules regulate cell-cell adhesions of human B cells. Submitted for publication.Google Scholar
- Martz, E., Davignon, D., KUrzinger, K., and Springer, T. A., 1982, The molecular basis for cytolytic T lymphocyte function: analysis with blocking monoclonal antibodies. Adv. Exptl. Biol. Med., 146:447.Google Scholar
- Ware, C. F., Sanchez-Madrid, F., Krensky, A. M., Burakoff, S. J., Strominger, J. L., and Springer, T. A., 1983, Human lymphocyte function associated antigen-1 (LFA-1): Identification of multiple antigenic epitopes and their relationship to CTL-mediated cytotoxicity. J. Immunol., 131:1182.PubMedGoogle Scholar