Immunological Tolerance. Part I of a Report of a Workshop on Foundational Concepts of Immune Regulation

Abstract

This report, the first of two, arose from a one-week workshop directed at discussing concepts of immune regulation, and focuses on immunological tolerance. We first outline the major ideas we thought sufficiently plausible to provide a context for discussing more controversial issues around tolerance. We then report on our discussion of different experiments that appear paradoxical in terms of the different, contemporary models of CD4 T cell inactivation/activation, and how such observations might be resolved in terms of insights provided by these contemporary models. These discussions bear on the plausibility of the Pathogen-Associated Molecular Pattern (PAMP), Danger and Two Step, Two Signal Models for the activation of naïve CD4 T cells. Some of the observations considered appear paradoxical in terms of the PAMP and Danger Models, but not with the Two Step, Two Signal Model. For example, genetically immunodeficient mice have been given foreign, sterile ectopic grafts, and the immune system allowed to develop once these grafts were well-healed in, and so in the absence of PAMPs or danger. The grafts were rejected, unexpected on the PAMP or Danger Models. We also discussed considerations and observations bearing on the widely held idea that antigen must crosslink the membrane Ig receptors of a B cell to initiate the generation of signal 1, or the alternative possibility that monovalent binding by antigen can do so. We favored the latter possibility, and discussed a particular model, "the Elbow Model," for how this might be achieved.

Does T Cell Activation Require a Quorum of Lymphocytes?

“…The authors concluded that the degree of antigenic disparity, among other factors, governs the ability of transplants to induce immunity and that, in the absence of sufficient disparity, tolerance ensues (41). These observations are consistent with the Quorum Hypothesis, even though it is unclear whether rejection requires a quorum of CD8, a quorum of CD4 T cells, or a quorum of a combination of the two types of T cells (42). The observations reported are not readily accounted for by the Danger Model, as this model posits that whether Ag activates/inactivates T cells depends upon whether danger is present/absent rather than the degree of foreignness of the Ag (42).…”

On how the immune system preferentially interacts with antigen‐specific molecules bound to antigen over unbound molecules, with emphasis on B cell receptor signalling

“…The binding of diverse ligands to the diverse variable regions of antibodies would have to cause the same structural change in the constant regions; otherwise, separate interaction sensing units would have to evolve that recognize each possible structural change, which is implausible. Given the high diversity of variable regions and given that antibody genes are assembled somatically, it is difficult to envisage how an allosteric mechanism can evolve that allows the same structural change to be induced in different antibodies on binding all ligands . Similar considerations apply to signalling by mIg of B cells and the TcR of T cells.…”

A Commentary on a Workshop ‘To Reveal the Foundational Concepts of Immune Regulation’ (i.e. Tolerance)

“…As illustration, let us look at the extent to which Bretscher's proposal of a two-step two-signal model for the activation of iTh (in his nomenclature, pTh or na€ ıve Th) solves these two problems (see Figure 1 in ref. [1]).…”