What Determines the Class of Immunity an Antigen Induces? A Foundational Question Whose Rational Consideration Has Been Undermined by the Information Overload

SIMPLE SUMMARY: Diverse studies suggest that the increased generation of information, as research intensity increases in a scientific field, leads to an “ossification of the canon” and the neglect of constructive “disruptive” research. I illustrate here how this has occurred in the context of a central question of immunology: what determines the class of immunity induced, cell-mediated immunity or antibodies, when a foreign antigen impinges upon a person or animal? I chose this question for three reasons. It is a basic question and has been the subject of intense research for at least the last three decades. The answer is central to the rational design of strategies of prevention and treatment in diverse areas of medicine related to the immune system: infectious diseases, cancer and allergies. Lastly, the predominant frameworks employed in analyzing this question by immunologists over these last three decades are implausible. Diverse observations on the variables of immunization, which affect the cell-mediated/antibody nature of the ensuing response, are paradoxical within their context. An alternative framework is consistent with these observations. Moreover, this alternative framework brings quantitative considerations to the fore and has considerable implications for treatment and prevention of clinical conditions in infectious diseases and cancer, as I discuss. ABSTRACT: Activated CD4 T helper cells are required to activate B cells to produce antibody and CD8 T cells to generate cytotoxic T lymphocytes. In the absence of such help, antigens inactivate B cells and CD8 T cells. Thus, the activation or inactivation of CD4 T cells determines whether immune responses are generated, or potentially ablated. Most consider that the activation of CD4 T cells requires an antigen-dependent signal, signal 1, as well as a critical costimulatory signal, initiated when a pattern recognition receptor (PRR) engages with a danger- or pathogen-associated molecular pattern (DAMP or PAMP). Most also envisage that the nature of the DAMP/PAMP signal determines the Th subset predominantly generated and so the class of immunity predominantly induced. I argue that this framework is implausible as it is incompatible with diverse observations of the variables of immunization affecting the class of immunity induced. An alternative framework, the threshold hypothesis, posits that different levels of antigen mediated CD4 T cell interactions lead to the generation of different Th subsets and so different classes of immunity, that it is compatible with these observations. This alternative supports a rational approach to preventing and treating diverse clinical conditions associated with infectious disease and, more speculatively, with cancer.