What Determines the Class of Immunity an Antigen Induces? A Foundational Question Whose Rational Consideration Has...

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.