Thoughts engendered by Bretscher's Two-step, Two-signal model for a peripheral self-non-self discrimination and the...

There are three questions under re-examination here that have been inspired by Bretscher's 'Two-step, Two-signal' model. First, what is the nature of the steps required in order for antigen-responsive cells to become effectors? Second, how does the immune system get started? Third and the most troublesome, what is the mechanism that relates the delivery of the two signals? To answer the first question, Bretscher proposes a pathway that I will place in another context by comparing it with what had been envisaged under the Associative Recognition of Antigen (ARA) model. The second question, how does the immune system gets started, is crucial to our understanding of the self-non-self discrimination. This problem boils down to, what is the origin of the first effector T helper (eTh) cells required to activate all antigen-responsive cells including the T helpers themselves (the primer problem)? To deal with this question, I proposed an antigen-independent pathway to primer eTh. Bretscher presents us with an antigen-dependent pathway to primer eTh. As competing models are precious in clarifying thinking and in guiding experimentation, I felt it important to reanalyse the two models and look for ways to decide between them. The third question deals with the requirement for and the mechanism of associative (linked) recognition of antigen (ARA). The concept of ARA is so compelling at both the experimental and theoretical levels that to save it, a new perspective will be introduced.