Tritope Model Research Articles

The case for allele-specific recognition by the TCR.

There is a sharp difference in how one views TCR structure-function-behaviour dependent on whether its recognition of major histocompatibility complex-encoded restriction elements (R) is germline selected or somatically generated. The generally accepted or Standard model is built on the assumption that recognition of R is by the V regions of the αβ TCR, which is not driven by allele specificity, whereas the competing model posits that recognition of R is allele-specific. The establishing of allele-specific recognition of R by the TCR would rule out the Standard model and clear the road to a consideration of a competing construct, the Tritope model. Here, the case for allele-specific recognition (germline selected) is detailed making it obvious that the Standard model is untenable.

Signaling interactions predicted by the Tritope model of the TCR.

As the data accumulates, it becomes obvious that the Standard Model of TCR structure-function relationships is in jeopardy. The proposed Tritope model has become more meaningful and, in any case, is richer in prediction and explanation. This is illustrated here by using the signaling interactions of the TCR as examples. An unsuspected signaling pathway for positive selection, and for alloreactivity, is predicted. Further, crucial data needed to elucidate the structural elements that distinguish signaling for restrictive- versus allo-reactivity are identified.

Contemplating Bretscher's View that the Tritope Model is 'Implausible'.

There is, at present, only two models of the TCR structure-function relationship. These are referred to here as the Standard (Centric) model and the Tritope model. While I have argued that the Standard model is untenable and proposed the Tritope to replace it, Bretscher has argued that the Tritope model is 'implausible' and throws his support for the Standard model. This essay analyses the implausibility argument concluding that it is unfounded.

Is the Framework of Cohn's 'Tritope Model' for How T Cell Receptors Recognize Peptide/Self-MHC Complexes and Allo-MHC Plausible?

Cohn has developed the tritope model to describe how distinct domains of the T cell receptor (TcR) recognize peptide/self-MHC complexes and allo-MHC. He has over the years employed this model as a framework for considering how the TcR might mediate various signals [1-5]. In a recent publication [5], Cohn employs the Tritope Model to propose a detailed mechanism for the T cell receptor's involvement in positive thymic selection [5]. During a review of this proposal, I became uneasy over the plausibility of the underlying framework of the Tritope Model. I outline here the evolutionary considerations making me question this framework. I also suggest that the proposed framework underlying the Tritope Model makes strong predictions whose validity can most probably be assessed by considering observations reported in the literature.

Dissecting the two models of TCR structure–function relationships

There are only two comprehensive models attempting to account for the TCR structure-function relationships, referred to as the Standard or Centric model (Model I) and the Tritope model (Model II). This essay is written to analyze comparatively the two formulations of restrictive reactivity, stressing in particular the logic of each. Model I is essentially built on an analogy between the TCR and the BCR. Given a TCR with only one combining site (paratope), restrictive recognition requires that its ligand be viewed as a composite structure between the peptide and restricting element. It is this relationship that entrains a set of correlates that makes Model I untenable. Model II is predicated on the postulate that the recognition of the allele-specific determinants expressed by MHC-encoded restricting elements (R) is germline encoded and selected, whereas the recognition of peptide (P) is somatically encoded and selected. These selective pressures must operate on definable structures and this, in turn, necessitates a multiply recognitive T cell antigen receptor (TCR) with independent anti-R and anti-P paratopes that function coherently to signal restrictive reactivity. The consequences of this "two repertoire" postulate give us a concept of TCR structure quite distinct from that at present generally accepted, as well as a surprising relationship between numbers of functional TCR V gene segments and allele-specific determinants in the species. In the end, both models must deal with the relationship between the epitope-paratope interaction(s) and the signals to the T cell necessary for its differentiation and function.

What would Treg-cell biology look like when viewed from a rationalized perspective?

The argument that Treg cells play a role in determining the Self (S)-Nonself (NS) discrimination (i.e. tolerance) is challenged based on two theoretical constructs, the two stage-two signal model for the S-NS discrimination and the Tritope model of TCR function. The conclusions are then tested by reinterpreting a published probing set of data purporting to show that Treg cells regulate tolerance. It is concluded that the major role of suppression is to operate as a feedback mechanism modulating the magnitude of the effector response; it is not a determinant of the S-NS discrimination (i.e. tolerance).

Challenging The Tritope Model of T cell Receptor Structure–Function Relationships with Classical Data on ‘Super’ and ‘Allo‐MHC’ Antigens

The response of the immune system to allo-MHC-encoded antigens and Mls 'superantigens' has been experimentally analysed in detail, but the data have not been coupled to a theoretical framework. It should therefore be instructive to see how well the newly proposed Tritope Model of TCR structure-function relationships deals with the signalling interactions between the TCR and the above antigens. We will pay heed to William Bateson's admonition, 'treasure the exceptions', by showing how a meaningful theory interrogates the data with the same validity that the data interrogate the theory. The concordances, as well as the contradictions, with the Tritope Model are a test of its heuristic value.

On Recognizing ‘Shades‐of‐Gray’ (Self–Nonself Discrimination) or ‘Colour’ (Integrity Model) by The Immune System

The aim is to discuss Cohn's T-cell receptor (TCR) Tritope model of recognition, propose a novel suggestion for prior-to-positive selection of thymocytes contributing to inherent major histocompatibility complex (MHC) reactivity of a T-cell repertoire and clarify the Integrity model about the function of the immune system. If we compare the perception of light with the recognition of nonself, we could imagine that the opacity might be a measure of docking interaction between specific receptors for antigen on T or B cells (TCR/peptide-MHC or BCR/antigen). From this viewpoint, the self-nonself discrimination (S-NS) metaphor would be perception of black (self) versus white (nonself). However, whereas detection of shades-of-gray suffices to describe S-NS discrimination principle, colour vision of the antigenic world portrays best the Integrity model. In concert with recognition of opacity, the Integrity model proposes detection of at least three colours (signals): red (harmful), blue (useful) and yellow (the rest, including homoeostatic ones). As a result, recognition of nonself is transferred into communication within self while deciding on type of the immune response. Hence, the S-NS discrimination model seems to be an oversimplification, because it fails to see colours and consequently lacks the need for suppressor/regulatory function. Similarly, the Danger model stops short of detecting being useful signals that confer immune asylum to helpful micro-organisms like commensals. I suggest that the immune system's repertoire for recognition, in general, has evolved by a novel drive called 'natural integrity' alongside natural selection, thus facilitating communication between cells of the immune system.

“Allorestriction” should be distinguished from “alloreactivity”

Whether or not allorestriction should be distinguished from alloreactivity depends on one's model of the TCR–ligand interaction. If the ligand is viewed as a determinant formed by a meld between peptide and the MHC-encoded restricting element, then the TCR, like the BCR, has a single combining site specific for the composite epitope (the Centric Model). If, however, one views the recognition of peptide and the MHC-encoded restricting element as independent, then interactions at two sites of the TCR must be integrated to signal the T cell (the Tritope Model). As TCR recognition of the MHC-encoded restricting element is, by definition, restricted (allele-specific), then under the Centric Model, all TCR signaling interactions with the composite epitope are due to allorestriction, which is peptide-specific. In contrast, under the Tritope Model, there are two classes of signaling interaction, allorestriction and alloreactivity. Alloreactivity is peptide-unspecific and is triggered by recognition of the allo-MHC-encoded restricting element allele. Alloreactivity is incompatible with the Centric Model, under which one would predict that it does not exist. Selected data are analyzed to illustrate the importance of this distinction.

The Tritope Model for restrictive recognition of antigen by T-cells: II. Implications for ontogeny, evolution and physiology

Based on the Tritope Model of the TCR [Cohn, M., 2005c. The Tritope Model for restrictive recognition of antigen by T-cells. I. What assumptions about structure are needed to explain function? Mol. Immunol. 42, 1419–1443], a set of functional and evolutionary problems surrounding restrictive recognition of antigen are discussed. These include the origin of allele-specific recognition, the selection pressures for polygeneism and polymorphism, the TCR signaling interactions, the centrality of effector T-helper (eTh)-dependence for activation, the role of haplotype exclusion, “nonclassical” MHC-elements, alloreactivity versus xenoreactivity, etc. Further, a set of observations believed to support the Standard Model are reinterpreted.

On the logic of positive selection

On the logic of positive selection

The Tritope Model for restrictive recognition of antigen by T-cells: I. What assumptions about structure are needed to explain function?

Given that the recognition of the allele-specific determinants expressed by MHC-encoded restricting elements (R) is germline encoded and selected, whereas the recognition of peptide (P) is somatically encoded and selected, then two different combining sites must be under selection. This necessitates a multirecognitive-single T-cell antigen-receptor (TCR) with anti-R and anti-P paratopes that function in concert to signal restrictive reactivity. The consequences of this “two repertoire” postulate not only gives us a concept of TCR structure quite distinct from that at present generally accepted, but, in addition, resolves many existent contradictions. The problems of the positive and negative selection, alloreactivity, Self–Nonself (S–NS) discrimination, the nature and size of the repertoire, and the related experimental interpretations, are discussed. Further the Tritope Model is compared with previously proposed models to justify why a competing model is warranted.

Tritope model of restrictive recognition by the TCR

Given that the recognition of the allele-specific determinants expressed by MHC-encoded restricting elements (R) is germline encoded and selected, whereas the recognition of peptide (P) is somatically encoded and selected, two different combining sites must be under selection. This necessitates a multiple recognitive single T-cell receptor (TCR) with anti-R and anti-P paratopes that function coordinately to signal restrictive reactivity. The consequences of this ‘two repertoire’ postulate provides a concept of TCR structure distinct from that generally accepted at present.