Abstract
T-lymphocyte activation displays a remarkable combination of speed, sensitivity, and discrimination in response to peptide–major histocompatibility complex (pMHC) ligand engagement of clonally distributed antigen receptors (T cell receptors or TCRs). Even a few foreign pMHCs on the surface of an antigen-presenting cell trigger effective signaling within seconds, whereas 1 × 105–1 × 106 self-pMHC ligands that may differ from the foreign stimulus by only a single amino acid fail to elicit this response. No existing model accounts for this nearly absolute distinction between closely related TCR ligands while also preserving the other canonical features of T-cell responses. Here we document the unexpected highly amplified and digital nature of extracellular signal-regulated kinase (ERK) activation in T cells. Based on this observation and evidence that competing positive- and negative-feedback loops contribute to TCR ligand discrimination, we constructed a new mathematical model of proximal TCR-dependent signaling. The model made clear that competition between a digital positive feedback based on ERK activity and an analog negative feedback involving SH2 domain-containing tyrosine phosphatase (SHP-1) was critical for defining a sharp ligand-discrimination threshold while preserving a rapid and sensitive response. Several nontrivial predictions of this model, including the notion that this threshold is highly sensitive to small changes in SHP-1 expression levels during cellular differentiation, were confirmed by experiment. These results combining computation and experiment reveal that ligand discrimination by T cells is controlled by the dynamics of competing feedback loops that regulate a high-gain digital amplifier, which is itself modulated during differentiation by alterations in the intracellular concentrations of key enzymes. The organization of the signaling network that we model here may be a prototypic solution to the problem of achieving ligand selectivity, low noise, and high sensitivity in biological responses.
Highlights
The functions of the adaptive immune system are regulated by intracellular signals arising from the interaction of clonally distributed, somatically generated receptors on T or B lymphocytes with antigens derived from invading infectious organisms [1,2]
The antigen receptors (T cell receptors or TCRs) on most conventional CD4þ and CD8þ T lymphocytes recognize short peptides extracted from pathogen proteins and displayed on cell surfaces in association with integral membrane proteins encoded by the major histocompatibility complex [3]
These enzymes are members of the mitogen-activated protein kinase (MAPK) family [20,31] and are attractive candidates for participating in such digital discrimination because prior studies have emphasized the importance of this pathway in both regulation of TCR signaling [27] and in functional responses [32], while other work with Xenopus oocytes has shown that the organization of this enzyme cascade can produce an ultrasensitive response associated with cell-fate decisions [33,34]
Summary
The functions of the adaptive immune system are regulated by intracellular signals arising from the interaction of clonally distributed, somatically generated receptors on T or B lymphocytes with antigens derived from invading infectious organisms [1,2]. Because the cellular machinery that creates pMHCs does not distinguish in most cases between pathogen proteins and host proteins, the surface of a cell that is being scanned by TCRs is typically a mosaic of self- and foreignpMHC ligands [4] This imposes a critical task on the T-cell recognition and intracellular signaling machinery, which is to avoid triggering functional responses to the highly abundant self-pMHCs while fostering rapid, highly sensitive, and specific responses to low densities of non-self-pMHCs on the same membrane. One major factor contributing to this discrimination by mature T cells is the elimination during thymic development of many immature cells possessing TCRs that are highly reactive with self-pMHCs [5,6]. This cellular selection itself depends on the capacity of the TCR to make fine distinctions between closely related pMHC structures when transducing signals that regulate cell survival and differentiation—distinctions that must be made by mature, post-thymic T cells
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