ReviewQuantitative challenges in understanding ligand discrimination by αβ T cells
Introduction
To fight viral or bacterial infections effectively without endangering their own viability, vertebrate organisms rely on the ability of their adaptive immune system to distinguish self from non-self agents. Among the many components of the adaptive immune system, the major CD4+ and CD8+ subsets of αβ T cells recognize antigens from these infectious organisms primarily in the form of peptides bound major histocompatibility complex-encoded molecules (pMHCs). The cellular processes that generate and load peptides onto MHC molecules, then export the resulting pMHC ligands to the cell surface for recognition by the receptors of T cells, do not generally discriminate between pathogen-derived and self-derived proteins or translation products. This leaves the critical task of ligand discrimination to the T lymphocyte itself—T cells must be able to be efficiently activated by infected or professional antigen presenting cells (APCs) bearing foreign ligands, while remaining for the most part in a naïve state upon interaction with normal (uninfected) cells.
This sharp discrimination has been documented experimentally both with functional assays (involving responses spanning hours to days, e.g. cytokine secretion, cytotoxicity, proliferation) or signaling assays (dealing with responses in the minute to hour range, e.g. calcium influx, kinase activity). These assays revealed that a T cell expressing a particular αβ receptor shows distinct responses to structurally related pMHC ligands, with a rather clear separation between agonists (which trigger T cell activation and are typically associated with receptor ligands derived from proteins of infectious agents) and non-agonists (which fail to trigger T cell activation and comprise the bulk of ligands with peptides derived from broadly expressed self proteins) (Davis et al., 1998, Germain and Stefanova, 1999). This distinction can be refined with subcategories of (1) strong agonists, which trigger all functions of T cells, even at low presentation levels, (2) weak/partial agonists which trigger T cells only when presented at very high dose and may stimulate only some of a cell's potential outputs, (3) antagonists, which not only fail to trigger functional responses from T cells but also may diminish activation-induced by agonist ligands when the two ligands are presented on the same APC, (4) synergistic endogenous peptides, which enhance the response of T cells to small quantities of agonist peptides, but fail to trigger these cells on their own (Krogsgaard et al., 2005), and (5) null ligands.
A major challenge in the field of ligand discrimination by T cells is the construction of a detailed, quantitative, mechanistic model that accounts for the ability of small differences in TCR-ligand binding to give rise to the extremely wide divergence in the dose–responses characteristic of closely related pMHCs interacting with the same TCR. Such model building is made difficult by the need to ensure that mechanisms implemented to account for threshold setting in response to variant pMHCs are also compatible with other known properties of T cell activation (namely its sensitivity and speed (Altan-Bonnet and Germain, 2005)).
In this review, we will discuss how ligand discrimination by T cells came to be viewed as the result of kinetic thresholding rather than allosteric regulation and present recent models showing how incorporating differential signaling feedback pathways into a kinetic proofreading scheme can explain the bulk of available results and predict new behaviors that have been verified by experiment. We will also discuss how these schemes potentially provide a quantitative explanation for adaptation of the ligand discrimination properties of T cells during their differentiation and maturation.
Section snippets
Ligand discrimination involving allostery: an Arlésienne with conceptual challenges
Activation of T lymphocytes is triggered by the engagement of their receptors (TCR) with pMHC ligands on the surface of antigen-presenting T cells. In contrast to co-evolved receptor–ligand pairs for which signaling secondary to ligand-induced conformational change can be easily understood to have been selected over long (evolutionarily relevant) time periods, there is no such genetic relationship between TCR fine specificity and ligand structure. This raises the question of whether it is
Theoretical understanding of ligand discrimination
For the sake of quantitatively understanding T cell ligand discrimination, theoreticians are thus left with the “lifetime dogma”, with the TCR–pMHC lifetime as the single biophysical parameter determining the functional activation of T cells. In fact, as the lifetime dogma emerged, specific quantitative models were proposed showing how exquisite ligand discrimination could be achieved when there were only “minute” biophysical differences in pMHC–TCR lifetimes between agonists and non-agonists.
Tunability of ligand discrimination in T cell activation
As argued above, it is difficult to reconcile with allosteric models of discrimination the ability of a pMHC ligand to be a non-agonist for a mature T cell but an agonist mediating positive selection for a developing thymocyte with the same TCR. Rather, these data imply that the relationship between the biophysical parameters of pMHC–TCR interaction and agonist activity is determined by the differentiation state of the T cell and that the discrimination threshold is actively altered during
Conclusion
In conclusion, we have reviewed several quantitative challenges to our understanding of ligand discrimination in T cells. Although conformational changes associated with the engagement of TCR with agonist pMHC have been suggested by many groups, they remain a working hypothesis needing experimental confirmation and must be accompanied by an explanation for how thymocytes and mature T cells with identical TCRs respond differently to the same pMHC ligand. Kinetic thresholding is the more dominant
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