Chapter 2 How the Immune System Achieves Self–Nonself Discrimination During Adaptive Immunity

We propose an “Avidity Model of Self–Nonself Discrimination” in which self–nonself discrimination is achieved by both central thymic selection and peripheral immune regulation. The conceptual framework that links these two events is the understanding that both in the thymus and in the periphery the survival or the fate of T cells is determined by the avidity of the interactions between T cell receptors (TCRs) on T cells, specific to any antigens and MHC/antigen peptides presented by antigen‐presenting cells (APCs). We envision that the immune system achieves self–nonself discrimination, during adaptive immunity, not by recognizing the structural differences between self versus foreign antigens, but rather by perceiving the avidity of T cell activation. Intrathymic deletion of high avidity T cell clones responding to the majority of self‐antigens generates a truncated peripheral self‐reactive repertoire composed of mainly intermediate and low but devoid of high avidity T cells compared with the foreign‐reactive repertoire. The existence of intermediate avidity self‐reactive T cells in the periphery represents a potential danger of pathogenic autoimmunity inherited in each individual because potentially pathogenic self‐reactive T cells are included in the pool of intermediate avidity T cells and can often be functionally activated to elicit autoimmune diseases. The distinct composition of peripheral T cell repertoires to self versus to foreign antigens provides a unique opportunity for the immune system to discriminate self from nonself, in the periphery, by selectively downregulating intermediate avidity T cells to both self and foreign antigens. Selective downregulation of the intermediate avidity T cell populations containing the potentially pathogenic self‐reactive T cells enables the immune system to specifically control autoimmune diseases without damaging the effective anti‐infection immunity, which is, largely, mediated by high avidity T cells specific to the infectious pathogens. In this regard, it has been recently shown that Qa‐1‐restricted CD8+ T cells selectively downregulate intermediate avidity T cells, to both self and foreign antigens, and as a consequence, specifically dampen autoimmunity yet optimize the immune response to foreign antigens. Selective downregulation of intermediate avidity T cells is accomplished via specific recognition, by the Qa‐1‐restricted CD8+ T cells, of particular Qa‐1/self‐peptide complexes, such as Qa‐1/Hsp60sp, which function as a common surrogate target structure and preferentially expressed on the activated intermediate avidity T cells. This regulatory pathway thus represents one example of the peripheral mechanisms that the immune system evolved to complete self–nonself discrimination that is achieved, imperfectly, by thymic negative selection, in order to maintain self‐tolerance. The conceptual framework of the “Avidity Model” differs from, but contains intellectual wisdom of certain conceptual elements of, the “Tunable Activation Thresholds Hypothesis,” the “Danger Model,” and the “Ergotypic Regulation Phenomenon.” It provides a unified and simple paradigm to explain various seemingly unrelated biomedical problems inherent in immunological disorders that cannot be uniformly interpreted by any currently existing paradigms. The potential impact of the conceptual framework of the “Avidity Model” on our understanding of the development and control of commonly seen autoimmune diseases is also discussed.