Recognition of self and regulation of specificity at the level of cell populations

It is suggested that immunologic specificity and selective responsiveness, assayed by effector and memory cells, are, in part, determined by the existing repertoire of lymphocytes and, in part, by the dynamic nature of cellular growth. Clones within horizontal networks resemble competing species in a Darwinian world. Upon stimulation, the development of a clone is greatly affected, in a dynamic way, by factors that determine the balance between self-renewal and differentiation. Antigen is a major factor. The amount of antigen and the nature of encounter with the immune system (sudden, graded or continuous), through the selection of a particular subset of clones, can be correlated with a weak or a strong expression of effector function and with the generation of effective memory or of tolerance. The encounter with self antigens obeys the same rules. Thus, the distinction between self and non-self is a quantitative one, both at the single-cell level and at the systemic level. The encounter of developing lymphocytes with self antigens, and in particular with idiotypes and MHC-antigens, restricts the repertoire and imposes major constraints both on the mode of interaction with foreign antigens and on potential self-recognition networks. The proposed "dynamic scheme", differing from "structural schemes" in a number of fundamental aspects, calls for reevaluation of present concepts of immunoregulation and for reinterpretation of data.