SMALL AMOUNTS OF SUPERANTIGEN, WHEN PRESENTED ON DENDRITIC CELLS, ARESUFFICIENT TO INITIATE T-CELL RESPONSES

Dendritic cells are potent antigen-presenting cells for several primar y immune responses and therefore provide an opportunity for evaluating the amounts of cell-associated antigens that are required for inducin g T cell-mediated immunity. Because dendritic cells express very high levels of major histocompatibility complex (MHC) class II products, it has been assumed that high levels of ligands bound to MHC products (' 'signal one'') are needed to stimulate quiescent T cells. Here we desc ribe quantitative aspects underlying the stimulation of human blood T cells by a bacterial superantigen, staphylococcal enterotoxin A (SEA). The advantages of superantigens for quantitative studies of signal on e are that these ligands: (a) engage MHC class II and the T cell recep tor but do not require processing; (b) are efficiently presented to la rge numbers of quiescent T cells; and (c) can be pulsed onto dendritic cells before their application to T cells. Thus one can relate amount s of dendritic cell-associated SEA to subsequent lymphocyte stimulatio n. Using radioiodinated SEA, we noted that dendritic cells can bind 30 -200 times more superantigen than B cells and monocytes. Nevertheless, this high SEA binding does not underlie the strong potency of dendrit ic cells to present antigen to T cells. Dendritic cells can sensitize quiescent T cells, isolated using monoclonals to appropriate CD45R epi topes, after a pulse of SEA that occupies a maximum of 0.1% of surface MHC class II molecules. This corresponds to an average of 2,000 molec ules per dendritic cell. At these low doses of bound SEA, monoclonal a ntibodies to CD3, CD4, and CD28 almost completely block T cell prolife ration. In addition to suggesting new roles for MHC class II on dendri tic cells, especially the capture and retention of ligands at low exte rnal concentrations, the data reveal that primary T cells can generate a response to exceptionally low levels of signal one as long as these are delivered on dendritic cells.