Phenotypic spandrel: absolute discrimination and ligand antagonism

Abstract

We consider the general problem of absolute discrimination between categories of ligands irrespective of their concentration. An instance of this problem is immune discrimination between self and not-self. We connect this problem to biochemical adaptation, and establish that ligand antagonism -the ability of sub threshold ligands to negatively impact response -is a necessary consequence of absolute discrimination.Thus antagonism constitutes a "phenotypic spandrel": a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of absolute discrimination displaying ligand antagonism, where antagonism strength is linear in distance from threshold. This contrasts with proofreading based models, where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simple model . The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and Fc RIs.

Multiple steady states and the form of response functions to antigen in a model for the initiation of T-cell activation

“…In addition it is important to know whether this model is consistent with all biological data and how it compares to other possible models for the same biological system. For a discussion of this we refer to [9], [6] and [10]. It was indicated in [10] that the situation where C N is a decreasing function of ν 1 cannot be reproduced using the model of [5].…”

Attack and defence in cellular decision-making: lessons from machine learning

“…To model cellular decision-making, we will use the general class of "adaptive sorting" or "adaptive proofreading" models, which account for many aspects of immune recognition [14,33], and can be shown to capture all relevant features of such cellular decision-making close to a decision threshold [34]. An example of such a model is displayed in Fig.…”

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

“…As a consequence kinase K is barely influenced by complex D m . As said before, there nevertheless still is some antagonism close to threshold when τ s ∼ τ which actually constitutes a smoking gun for absolute discrimination mechanisms (see next section for experimental evidence and [22] for a more careful study) . Antagonism is illustrated on Fig.…”

“…2b, while specificity is conserved, the system loses sensitivity to minute concentrations of ligands. It can be shown mathematically that antagonism is a necessary consequence of absolute discrimination, qualifying as a "phenotypic spandrel" [22]. Intuitively, absolute discrimination necessarily requires some internal variable (similar to kinase K ) to discriminate between ligands with different τ s irrespective of their concentration, and as a consequence antagonism will always occur when those internal variables are activated by subthreshold ligands.…”

“…Intuitively, absolute discrimination necessarily requires some internal variable (similar to kinase K ) to discriminate between ligands with different τ s irrespective of their concentration, and as a consequence antagonism will always occur when those internal variables are activated by subthreshold ligands. A model performing perfect absolute discrimination is presented in [22], as well as a simple categorization of antagonistic effects, that can be increased or mitigated as τ → 0 depending on the model considered.…”