Monoclonal antibodies to LFA-1 and to CD4 inhibit the mixed leukocyte reaction after the antigen-dependent clustering of dendritic cells and T lymphocytes.
T cell proliferation in response to many stimuli is known to occur in discrete clusters of dendritic cells (DC) and CD4+ helper lymphocytes. The role of lymphocyte function-associated antigen (LFA-1) and CD4 in the formation and function of these clusters has been evaluated in the mixed leukocyte reaction (MLR). By day 1 of the control MLR, most of the DC and responsive T cells are associated in discrete aggregates. Addition of anti-LFA-1 and CD4 reagents does not block DC-T aggregation but reduces the subsequent proliferative response by 80-90%. Anti-LFA-1 disassembles newly formed DC-T cell aggregates, whereas anti-CD4 inhibits blastogenesis without disrupting the cluster. Binding of DC to sensitized, antigen-specific CD4+ cells has been studied using lymphoblasts isolated at day 4 of the MLR. It has been shown previously that greater than 80% blasts rebind to DC in an antigen-specific fashion in rapid (10 min) binding assays. Antigen-dependent DC-T binding is blocked by anti-Ia but not by mAb to LFA-1 or CD4. However, the bound anti-CD4-coated lymphocytes are unable to release IL-2. Anti-LFA-1-coated T cells release IL-2 but are easily disaggregated after binding to DC. These findings lead to two conclusions. LFA-1 and CD4 are not involved in the initial steps whereby DC bind to T cells but exert an independent and subsequent role. LFA-1 acts to stabilize the DC-T cluster, while CD4 contributes to lymphocyte blastogenesis and IL-2 release. Because DC but not other presenting cells cluster unprimed lymphocytes, it seems likely that an antigen-independent mechanism distinct from LFA-1 and CD4 mediates aggregate formation at the onset of cell-mediated immunity.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000954:Antigens, Surface / Q000276:immunology*; D002448:Cell Adhesion; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D007376:Interleukin-2 / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1