Localization dose and time of antigens determine immune reactivity

Two models to explain patterns of immune reactivity of T and B cells are compared: the two-signal theories and the antigen-localization-dose-time and structure concept. The two-signal theory states that signal 1 (= antigen alone signalling via specific T or B cell receptor) turns T and B cells off, signal 1 plus co-stimulatory signals 2 induces them. Our model employs immuno-reactivity antigen parameters, i.e. localization-dose-time kinetics and structure of antigen in determining T and B cell reactivity. Both concepts have in common that immune reactivity is somatically learned and not germline defined and that there is nothing unique to the antigenic structure itself that could distinguish self from nonself antigens. While two-signal theories base positive versus negative reactivity on the presence or absence of co-stimulatory signals anywhere in the body, our alternative model proposes that besides antigen structure, dose and time it is the localization of antigen--vis-à-vis the organized lymphoid tissues--that determines reactivity patterns as follows. First, antigen that does not reach secondary lymphoid organs in minimum doses or for sufficiently long time periods, is immunologically ignored. Second, antigen that either usually exists in the lymphoid system or reaches it and persists in excessive amounts for long periods deletes T cells. Third, antigen that is transported to secondary lymphoid organs in sufficient (but not excessive) amounts and for a sufficient time period (but does not persist) induces an effective immune response. B cell responses are also induced exclusively in lymphoid tissues. Short-term B cell responses are T independent against antigens linked to bacterial lipopolysaccharides or against highly repetitive and strictly ordered antigens; thus, B cells are pattern recognizers (monomeric antigens usually accessible to B cells are in general likely to be self-antigens. Strictly ordered repetitive antigens are virtually by definition infectious agents). Long-term (switched) B cell responses against mono- and polymorphic antigens are T cell dependent regulated by time dose and localization of antigen.