Feedback suppression of immune responses involves a complex series of interactions initiated by products of the response itself. The long-term objective of the present study is to understand the mechanisms by which such end products ultimately suppress the response which produce them. To this end, an in vitro model of a feedback suppression pathway has been developed which is activated by a primed B-cell product. In this system, suppression depends upon the activation by this product of a defined T-cell subset. The intent of the present research is to establish the mechanisms by which these """"""""suppressor"""""""" T cells are activated and to identify any differences in these mechanisms which may exist in the activation of primed versus unprimed T-cell populations. This will be approached first by specifically characterizing the activating molecule(s) and then by defining its interaction with the receptors on purified unprimed or primed T suppressor cell precursors. The activating molecule(s) will be analyzed for kinetics and requirements of secretion, and the nature of the secreting B cell will be determined using supernatants from immune B cells. These supernatants can replace the immune B cell in activating suppression. Affinity chromatography and cellular adsorbents will be used to determine the nature and specificity(s) for antigen and potential target cells of the active molecule(s). Separation procedures will be established for purifying the suppressor cell precursor subpopulation which will then be tested for the activity of its receptors for the activating molecule and for its determinant specificity. We have found that primed T-cell populations exhibit no suppressive activity in response to the same activating molecules which induce severe suppression in the presence of unprimed T-cell populations. Primed T-cell populations will, therefore, be purified as above and tested separately to determine the cause of their loss of reactivity. Understanding these mechanisms of natural control of normal immune responses should provide important insights into diseases deriving from immune over- or under-responsiveness as well as clarifying how a response to one immunogen may affect responsiveness to subsequent challenge with the same or a different immunogen. (LB)
