Monomeric TCRs drive T cell antigen recognition

Brameshuber, Mario; Kellner, Florian; Rossboth, Benedikt K.; Ta, Haisen; Alge, Kevin; Sevcsik, Eva; Göhring, Janett; Axmann, Markus; Baumgart, Florian; Gascoigne, Nicholas R. J.; Davis, Simon J.; Stockinger, Hannes; Schütz, Gerhard J.; Huppa, Johannes B.

doi:10.1038/s41590-018-0092-4

Cited by 118 publications

(117 citation statements)

References 62 publications

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“…Based on our results we propose that signaling-competent TCR assemblies can be created either via parallel engagements by closely spaced high-affinity ligands or via serial, rapid and short-lived engagements by a single nominal pMHC. This notion integrates well with recent findings on TCR triggering by pMHC 6,17 as well as artificial ligands 15,16 and reconciles the frequently observed relevance of TCR clustering 35 with the single molecule sensitivity of sensitized antigen detection 18 .…”

Section: Discussionsupporting

confidence: 88%

“…Spatially well-separated pMHC:TCR binding events were observed to elicit T-cell activation 17 , and even in T-cell induced microclusters individual pMHCs are not in close molecular proximity 6 .…”

Section: Introductionmentioning

confidence: 99%

“…YOYO was removed using 100 kDa AmiconUltra centrifugal filters and DNA origami-bearing SLBs were produced as described above. Positions of diffraction-limited spots were determined for both color channels and corrected for chromatic aberrations as described 6 . Detected signal positions were counted as colocalized if signals were within a distance of 240 nm.…”

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confidence: 99%

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DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Hellmeier

Platzer

Eklund

et al. 2020

Preprint

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T-cells detect with their T-cell antigen receptors (TCRs) the presence of rare peptide/MHC complexes (pMHCs) on the surface of antigen presenting cells (APCs). How they convert a biochemical interaction into a signaling response is poorly understood, yet indirect evidence pointed to the spatial antigen arrangement on the APC surface as a critical factor. To examine this, we engineered a biomimetic interface based on laterally mobile functionalized DNA origami platforms, which allow for nanoscale control over ligand distances without interfering with the cell-intrinsic dynamics of receptor clustering.We found that the minimum signaling unit required for efficient T-cell activation consisted of two ligated TCRs within a distance of 20 nanometers, if TCRs were stably engaged by monovalent antibody fragments. In contrast, antigenic pMHCs stimulated T-cells robustly as well-isolated entities. These results identify the minimal requirements for effective TCR-triggering and validate the exceptional stimulatory potency of transiently engaging pMHCs.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Hellmeier

Platzer

Eklund

et al. 2020

Preprint

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“…Third, the oligomerization of the TCR has been observed biochemically and suggested to improve sensitivity . However, microscopy‐based techniques have failed to observe TCR oligomers instead suggesting that the TCR remains monomeric . Finally, nanometer‐scale clustering of the TCR, as distinct from a physically associated oligomeric state, may effectively increase the on‐rate for binding by increasing the local concentration of TCR …”

Section: Mechanisms Of T‐cell Sensitivity To Antigenmentioning

confidence: 99%

Molecular mechanisms of T cell sensitivity to antigen

Siller-Farfán

Dushek

2018

Immunological Reviews

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T cells initiate and regulate adaptive immune responses that can clear infections. To do this, they use their T cell receptors (TCRs) to continually scan the surfaces of other cells for cognate peptide antigens presented on major histocompatibility complexes (pMHCs). Experimental work has established that as few 1-10 pMHCs are sufficient to activate T cells. This sensitivity is remarkable in light of a number of factors, including the observation that the TCR and pMHC are short molecules relative to highly abundant long surface molecules, such as CD45, that can hinder initial binding, and moreover, the TCR/pMHC interaction is of weak affinity with solution lifetimes of approximately 1 second. Here, we review experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity. We organize the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that (a) promote TCR/pMHC binding, (b) induce rapid TCR signaling, and (c) amplify TCR signaling. We discuss work showing that high sensitivity reduces antigen specificity unless molecular feedbacks are invoked. We conclude by summarizing a number of open questions.

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“…Similarly, oligomeric clusters of TCR seen in antigen-experienced T cells have been implicated in their enhanced production of cytokines (12). But, recent reports argue that TCR is randomly distributed on the plasma membrane of antigen-experienced cells in monomeric state (13) and that they exclusively drive antigen recognition (14). An immediate outcome of antigen recognition and supra-threshold TCR signalling in rapidly migrating, poorly adhesive T cells is the formation of an immature immunological synapse (IS) (15).…”

Section: Introductionmentioning

confidence: 99%

Synapse propensity of human memory CD8 T cells confers competitive advantage over naïve counterparts

Mayya

Judokusumo

Abu-Shah

et al. 2018

Preprint

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2Memory T cells are endowed with multiple functional features that enable them to be more 3 protective than naïve T cells against infectious threats. It is not known if memory cells have a 4 higher synapse propensity, i.e. increased probability to form immature immunological 5 synapses that then provide an entry into different modes of durable interaction with antigen 6 presenting cells. Here we show that only human memory CD8 T cells have remarkably high 7 synapse propensity compared to naïve counterparts. Such a dichotomy between naïve and 8 memory cells is not observed within the human CD4 or murine CD8 T cell population. 9 Increased surface expression of LFA1 contributes to the higher synapse propensity in human 10 memory CD8 T cells. Finally, we show that higher synapse propensity in human memory 11 CD8 T cells allows them to compete out naïve CD8 T cells from getting recruited to the 12 response. This observation has implications for original antigenic sin and aging of the 13 immune system in humans. 14 15

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Monomeric TCRs drive T cell antigen recognition

Cited by 118 publications

References 62 publications

DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Molecular mechanisms of T cell sensitivity to antigen

Synapse propensity of human memory CD8 T cells confers competitive advantage over naïve counterparts

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