Phenotypic models of T cell activation

Lever, Melissa; Maini, Philip K.; Merwe, P. Anton van der; Dushek, Omer

doi:10.1038/nri3728

Cited by 143 publications

(210 citation statements)

References 97 publications

(137 reference statements)

Supporting

Mentioning

203

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, a subset of studies have suggested that the optimal pMHC affinity may be less pronounced at high pMHC doses (13,22). The mechanism underlying an optimal pMHC affinity (or half-life) is proposed to be a tradeoff between serial binding and kinetic proofreading, but we have recently shown that this trade-off would lead to an optimal pMHC affinity at all pMHC doses (9).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

View full text Add to dashboard Cite

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

show abstract

mentioning

confidence: 99%

“…It is also appreciated that the pMHC dose determines, for example, the peripheral induction of regulatory T cells (4,5). Although the proteins that form the TCRregulated signaling network have been identified (6,7), it remains unclear how the architecture they form integrates the pMHC affinity and dose into T-cell activation (8,9).…”

mentioning

confidence: 99%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

View full text Add to dashboard Cite

show abstract

“…This effect is debated, since strong binding TCRs evolved in vitro, with τ s of the order of 50 to 100 s conversely yield an exceptionally potent response [15]. Lever et al recently reviewed and compared 5 families of models [42], including the one from previous section, and suggested that a mid-range τ can be simply explained by a kinetic proofreading with "limited signalling", meaning that the signalling complex in the cascade gets inactivated with constant rate. However, this model does not include the negative feedback described here, and thus do not display antagonism.…”

Section: Beyond Absolute Discrimination?mentioning

confidence: 99%

“…Taylor et al [59] [59]. As of 2015, although the structural details of the early events in immune recognition by T cells remain elusive, the consensus around the lifetime dogma is thus holding and it is enabling physicists to build biochemically-explicit or phenotypic models of good biological significance [2,23,42]. It constitutes a rich paradigm for both theoretical and experimental biophysical considerations, and most of our discussion will be within this framework.…”

Section: Antigen Discrimination Is Set By the Lifetime Of The Antigenmentioning

confidence: 99%

“…It should thus be first pointed out that many (if not all) molecular components of the original McKeithan model [47] are indeed present in actual cells. Such "realistic" model explains its popularity and its use as a blueprint for many current models of immune decision [42]. The phosphorylation cascade would correspond to the known phosphorylation of Internal Tyrosine Activation Motifs (a.k.a.…”

Section: Biologically Realistic Models For Immune Detectionmentioning

confidence: 99%

See 1 more Smart Citation

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

François

Altan‐Bonnet

2016

J Stat Phys

View full text Add to dashboard Cite

Some cells have to take decision based on the quality of surroundings ligands, almost irrespective of their quantity, a problem we name "absolute discrimination". An example of absolute discrimination is recognition of not-self by immune T Cells. We show how the problem of absolute discrimination can be solved by a process called "adaptive sorting". We review several implementations of adaptive sorting, as well as its generic properties such as antagonism. We show how kinetic proofreading with negative feedback implement an approximate version of adaptive sorting in the immune context. Finally, we revisit the decision problem at the cell population level, showing how phenotypic variability and feedbacks between population and single cells are crucial for proper decision.

show abstract

Epitopes

Kirpach

2015

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

T and B lymphocytes, the mediators of adaptive immune responses, express antigen‐specific receptors that allow them to discriminate between self and a virtually unlimited number of nonself molecules. Their receptors specifically recognise and bind subdomains of foreign macromolecules which are called epitopes. T‐cell epitopes (TCEs) and B‐cell epitopes (BCEs) differ fundamentally in the way they are recognised by the immune system. BCEs are recognised as three‐dimensional structures on the surface of native antigens. TCEs are parts of internalised and processed antigens that are presented to T lymphocytes in association with molecules of the major histocompatibility complex. As in a biological system T‐ and B‐cell receptors or antibody molecules face a virtual infinite number of structures, cognate interactions with epitopes are the basis of the primordial intelligence that drives the teleological choices of the immune system. Immunodominance directs the immune response towards selected epitopes. Key Concepts Surface immunoglobulins of B cells and antibodies recognise the B‐cell epitope (BCE) of an antigen in its native conformation, while T‐cell receptors (TCRs) recognise the T‐cell epitopes (TCEs) only after intracellular processing of the antigen, and in association with major histocompatibility complex (MHC) molecules. The main common feature of B‐cell epitopes is accessibility on the surface of the antigen. TCE peptides that bind to the same allele of MHC molecules share common ‘anchor’ residues (motifs) that contact the MHC molecule. TCEs presented by MHC class II molecules are longer and more variable in size and their anchor residues are less well defined than those of peptides presented by MHC class I molecules. Patterns of anchor residues facilitate the prediction of peptide binding to MHC molecules. The TCR–MHC–peptide tripartite cognate interaction in concert with coreceptors and other signalling modules mediate T‐cell activation. Immunodominance refers to the concept that only a small subset of the potential epitopes (TCEs or BCEs) present in a given antigen elicit an immune response. Mimotopes are small molecules that mimic the structure of complex conformational epitopes without any sequence homology. While TCEs can be predicted with some confidence, ill‐defined characteristic features of BCEs limit their predictability. Epitope‐based vaccines will allow to better manage desired and undesired cross‐reactivity.

show abstract

Phenotypic models of T cell activation

Cited by 143 publications

References 97 publications

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

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

Epitopes

Contact Info

Product

Resources

About