Immunological self/nonself discrimination: integration of self vs nonself during cognate T cell interactions with...

The hypothesis is presented that immunological integration of nonefficacious vs efficacious T cell antigen receptor (TCR) signals are foundational for self/nonself discrimination and that multiple integrative mechanisms are intrinsic to the molecular to molar organization of an adaptive immune response. These integrative mechanisms are proposed to adaptively regulate expression of costimulatory signals, such that foreign proteins are associated with the expression of costimulatory signals, whereas self-proteins are associated with the lack of costimulatory signaling. Overall, this model offers several unique contributions to the study of immunology. First, this model postulates that cognate TCR/major histocompatibility complex (MHC) interactions are sufficient to adaptively mediate immunological self/nonself discrimination. This model thereby offers a unique alternative to models that largely rely on innate immunity to prime immune discrimination. Second, the integrative model argues that the immune system can simultaneously reinforce self-tolerance and promote immunity to foreign organisms at the same time and in the same location. Many alternative models presume that pathogenic self-reactive T cells do not exist at the outset of an immune response against foreign agents. Third, the integrative model uniquely predicts relationships between immunodeficiency and autoimmune pathogenesis. Fourth, this model illustrates the regulatory advantages of cognate antigen presenting cell (APC) systems (i.e., T cell or B cell APC) compared to nonspecific APC. Cognate APC systems together with the respective clonotypic responders may comprise a fundamental "network" of lymphoid cells. Such networks would have clone-specific regulatory capabilities and may be central for immunological self/nonself discrimination. Fifth, this model provides an explanation for "infectious" tolerance without creating specialized subsets of "suppressor" or "regulatory" T cells. Each mature T cell retains the potential to reinforce tolerance or mediate immunity, depending on the specific antigenic cues present in the immediate environment.