Recognition of self, balance of growth and competition: Horizontal networks regulate immune responsiveness

This report addresses itself to two fundamental questions: the generation of immunologic specificity, and the regulation of cellular growth. The classical clonal selection theory and later schemes involving lymphocyte networks or “circuits” postulate sets of specific “recognition” events which directly determine the nature of the immune response. An alternative principle is offered to apply to the analysis of immune phenomena: namely, that of a Darwinian dynamic selection among lymphocyte populations differing in their relative “fitness”. Incremental selection pressure upon a diverse population is, in theory, capable of producing a precisely specific outcome, and this can account for the fine specificity of the immune response. The immune system is described in terms of “horizontal” networks. A network consists of lymphocyte clones regulated by feedback mechanisms which manifest cross‐reactivity, resulting in competition and selection. The relative “fitness” of clones within a network depends primarily on their growth capacities, as assessed by the “balance of growth” hypothesis: accordingly, the number of divisions of an antigen‐responsive lymphocyte and the probability of maturation depend on regulatory factors. In particular, (a) activated, but not “resting” cells, can be further induced to mature or regenerate the relative probability of maturation increases with antigen dose and with affinity (avidity); (c) the in vivo induction of “terminal differentiation” of both B and T cells is antagonistic to clonal expansion; and (d) both activation and maturation are threshold‐dependent in terms of antigen dose and avidity, the threshold for maturation being generally higher. The hypothesis implies that proliferation can be uncoupled from differentiation under certain predictable conditions. Moreover, clones that proliferate for prolonged periods of time without significant maturation into effector cells may reach prominence. This mode of “latent proliferation” plays a major role in the selection and expression of the immune repertoire: those T or B cells are selected that react “proliferatively” with certain classes of self antigens and this constraint ensures tolerance to self. Major histocompatibility complex restriction and alloreactivity follow essentially as expressions of heteroclicity in this selection. Proliferative, latent reactions can mediate generation and maintenance of memory and tolerance and determine the ratio of helper to suppressor cells. The proposed scheme is amenable to testing and has many theoretical and experimental implications.