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 αß 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.

The real "danger" lies in the failure to confront fundamentals.

Can we formulate a framework that would provide an agreed upon basis for discussions of immune behaviour? An attempt to do this is, in the end, the main goal of this essay. If you tell a physicist that you have invented a perpetual motion machine, he would not spend any time trying to reveal the flaw. Rather, he would shrug you off because in his framework, such a machine is an impossibility. However, immunologists lacking an agreed upon, preferably default, framework spend their time chasing into dead-end alleys or take refuge in descriptive empiricism. This will be illustrated using Danger theory, which ignores fundamentals to generate a framework believed to obviate the need for a Self (S)-Nonself (NS) discrimination and which is claimed to be bolstered with monogamous data (observation married to a single explanation). The arguments presented here apply to all NS-marker theories (pathogenicity, discontinuity, localization, danger, etc.).

Exploring the elements for a successful immune offense against cancer.

A successful immune attack on a tumor requires two elements. First, a nonself (NS) epitope that can act as an effective target must be expressed uniquely and uniformly on the tumor. Second, the immune system must be induced to produce an appropriate ridding effector activity specific for the cell expressing that de novo displayed NS-epitope. Today, the major effort is directed toward nonspecifically increasing the horsepower of the immune system by relieving suppressive and resistance factors using checkpoint blockade. This is coupled to the hope that the cancer will display a unique nonself determinant and that tolerance to Self (S) will not be abrogated. Here, these two elements will be explored in order to see what a more defined approach to the immune system treatment of cancer entails. While a Hail Mary approach may, in the end, be our only alternative, defining the elements of a solution, attainable or not, based on basic immunology, can only be salutary.

Rationalizing the path to a universal graft recipient.

The goal of this essay is to take the reader through the logic that would predict universal graft acceptance. The story begins with what we learned from an experiment performed 65 years ago and develops that information in greater depth. The pathway of the analysis leads to the conclusion that controlling the immune system at the level of the T-helper would be the best way to approach a general solution to the problem of graft acceptance.

History of the antibody workshops.

At a critical period in the history of contemporary immunology, a handful of biochemists and fringe immunologists formed a group known as the Antibody Workshop. They had a major impact on the field by attracting molecular biologists who worked to reduce the study of cellular and organ level immunology to the molecular level. This had a dramatic effect on the field both conceptually and practically by providing the targets for clinical manipulation. The story of the origin and development of this group over time is recounted here.

An observation that illustrates most T cell receptor structure-function relationships.

The Standard model of the T cell receptor (TCR) structure-function relationships is based on an analogy with the B cell receptor. Here a single observation is analyzed to show why this appears to be untenable. The Standard model cannot account for allele-specific recognition of theMHC-encoded presenter of peptide (R) by the TCR nor can it adequately explain alloreactivity. The competing framework is based on the assumptions that (1) single V-domains recognize the alleles of R, (2) restrictive reactivity is peptide specific, whereas alloreactivity is peptide unspecific, and (3) the TCR is born in two conformations, which display reciprocal behaviors (see text). In any case, whatever position one takes regarding these two models, competing conceptualizations are of crucial value in guiding experimentation, not to mention creative thinking.

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.

Learning from a contemporary history of immunology.

This essay is a selected aspect of the history of contemporary immunology seen from a "what can we learn" point of view. It is limited to the ideas and experiments from which we might draw a take-home message. The emphasis is on the convoluted pathway that was actually used by immunologists to arrive at understanding compared to the direct pathway that could have been used given the knowledge at that time. It takes the reader through the instructionist era of the 1940s to the present by stressing the elements of thinking most conducive to the arrival at a default understanding of the intact immune system. It is a personalized account because the author participated directly in the debates that led eventually to agreed-upon or default conceptualizations. Given this, a peek at the future is attempted as a test of the validity of a Cartesian or reductionist approach to arriving at simplification of complexity and at the maximizing of generalization. A reasoned guess (i.e., a theory) is the only way we have to understand the world around us.

Core principles characterizing immune function.

The immune system is an anticipatory mechanism designed by evolution to protect the individual against noxious agents and harmful cellular debris. In order to recognize substances that it has never encountered, the immune system somatically generates an appropriately sized random (with respect to self and nonself [NS]) recognitive repertoire that is coupled to a biodestructive and ridding output. Consequently, a Self-NS discrimination is required in order to avoid autoimmunity. This essay is an attempt to highlight the core principles upon which this anticipatory mechanism depends in order to function.

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.

Rationalizing thymic selection for functional T-cells: A commentary.

What are the minimum specificity requirements of a thymic selective process that establishes (1) restrictive recognition of peptide, (2) the Self (S)-Nonself (NS) discrimination, and (3) the categories of effector function? Given an answer to that question, how well does it fit with the observed selective processes in thymus where T-cells are generated? Any discrepancies between the two must be rationalized. The goal of this essay is to attempt just that.

Two unresolved problems facing models of the Self-Nonself discrimination.

Although the Associative (linked) Recognition of Antigen (ARA) model for a Self (S)-Nonself (NS) discrimination, now over 50 years old, is built on a solid conceptual and experimental base, two unsettled questions remain. In examining these questions, unanticipated aspects of the ARA Model itself had to be reconsidered. This essay spells out these problems and suggests possible solutions.

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).

Analysis of Paris meeting redefining the "self" of the immune system.

Some ideas because of their intuitive appeal never die by neglect and survive because they are not amenable to experimental disproof. They can only be evaluated by weighing them against competing ideas and by invoking a credibility factor when used to explain observation. Most scientists would recommend ignoring such ideas, yet there is much to be learned by engaging their proponents in debate. The immune system viewed as an idiotype network, and its tweaking by the new school of "contextualists" is an example of such an idea. As chance would have it, the supporters of this idea gathered in a meeting, thereby permitting a cumulative analysis of this conceptualization. The goal of this essay is to compare the views of each of the speakers in light of a competing theory with the hope that a better understanding of immune responsiveness will emerge.

Autoimmunity: Rationalizing possible pathways from initiation to disease.

Any physiological system that has as its output an activity that is biodestructive and ridding must have a way of distinguishing the host (self) from that which is other (nonself). The setting in which autoimmunity can be analyzed depends, in part and unavoidably, on the way in which the normal self (S)-nonself (NS) discrimination is accomplished. Any discussion of autoimmunity should include one's view of this latter. To this end, a pathway for the normal S-NS discrimination will be proposed. Then, a mechanism for the determination of effector class will be considered as autoimmune disease is consequent to it. Experiments challenging both the proposed model of normal behavior, as well as that of the extrapolation to autoimmunity, will be cited along with a discussion of some of the elements which, if rendered defective, would result in autoimmunity. The goal is to see how far this particular abstraction based largely on the logic of evolutionary biology can meaningfully guide understanding of the disease.

The Institut Pasteur attic dwellers: their origins, their paths to discovery.

Although this volume is dedicated to honoring François Jacob, I would like my contribution to broaden the context by recalling the background within which the scientists of those times operated. The specific scientific accomplishments of Jacob will certainly be covered by the other contributors who collaborated with him. My handful of recollections presented here largely as vignettes is intended to give the reader a feeling for the elements, many social, that shaped the generation of scientists that included such central figures, Jacob, Lwoff, Monod. It is the tale of a generation trying to express its creativity in a world caught up in war, irrational values and unforgivable inhumanity. Even this limited account is a great story bringing us important lessons for thought.

A stepwise model of polyreactivity of the T cell antigen-receptor (TCR): its impact on the self-nonself discrimination and on related observations (receptor editing, anergy, dual receptor cells).

The existence of antigen-receptors, BCR, and T cell antigen-receptors, that are "polyreactive", necessitates a rethinking of its effect on two problems faced by the "adaptive" immune system: the self (S)-nonself (NS) discrimination and the determination of effector class. Here, we will concentrate on the impact of polyreactivity on the S-NS discrimination. The anti-S cells interacting with S (i.e., responding to Signal 1) are on the pathway to inactivation. Before irreversibility sets in, these cells can be activated by a second signal (Signal 2) from an effector T-helper (eTh). As these polyreactive anti-S cells express anti-NS specificities, they can be activated by recognition of NS-epitopes in the host's normal immunogenic load with the potential to result in autoimmunity. This problem is delineated using a discrete structural model, the corollaries of which are: (1) a two-step pathway for the purging of anti-S cells (i.e., the S-NS discrimination), and (2) defensible contexts within which to view the phenomena of receptor editing, anergy, and dual receptor cells.

What is so special about thinking; after all, we all do it!

Understanding the adaptive immune system can be simplified by treating it as three linked modules, the generation of the recognitive repertoire, the sorting of the repertoire by purging anti-self, and the coupling of the repertoire to appropriate effector mechanisms. Each of these modules has a unique database and a logic that is determined by evolutionary considerations founded on value versus harm. Selection cannot operate to perfection, only to adequacy, meaning not limiting to the procreation of the species. Consequently, this system has limits in that it fails, by human standards, to adequately protect against a variety of pathogens and, even when protecting successfully against others, all too often initiates autoimmunity and innocent bystander pathology. What evolution trivializes defines the subject called clinical immunology. If we wish to deal with the pathology that evolution views to be of an acceptable frequency, then we had best first understand what it did give us as a sufficiently functional system, namely the decision pathways of the three modules and in what ways their protective outputs are limited.

"Allorestriction" should be distinguished from "alloreactivity".

Whether or not allorestriction should be distinguished from alloreactivity depends on one's model of the TCR­ligand 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.

Ten experiments that would make a difference in understanding immune mechanisms.

Jacques Monod used to say, "Never trust an experiment that is not supported by a good theory." Theory or conceptualization permits us to put order or structure into a vast amount of data in a way that increases understanding. Validly competing theories are most useful when they make testably disprovable predictions. Illustrating the theory-experiment interaction is the goal of this exercise. Stated bleakly, the answers derived from the theory-based experiments described here would impact dramatically on how we understand immune behavior.