Potent T cell agonism mediated by a very rapid TCR/pMHC interaction

Boulter, Jonathan M.; Schmitz, Nicole; Sewell, Andrew K.; Godkin, Andrew; Bachmann, Martin F.; Gallimore, Awen

doi:10.1002/eji.200636743

Cited by 35 publications

(33 citation statements)

References 30 publications

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“…2b and Table II). The binding affinity of P14 TCR to gp33/D b is within normal range for other TCR-pMHC I interactions reported (1,46), but slightly lower than the previous report (2.3 M) (44).…”

Section: The P14 Tcr-gp33/d B Interaction Features Low Binding Affinisupporting

confidence: 78%

“…A similar correlation of affinity activity was implied by Holler and Kranz (25) using transfected hybridomas, but a sigmoidal curve was not seen in their system. In addition to cytolysis and cytokine production, T cell proliferation was recently reported to correlate to affinity (leaving out those peptides that do not stabilize MHC well) also using P14 TCR (44). Because the binding of P14 TCR and cognate pMHCs is very fast, to make sure that binding kinetics are accurate, we also tried a few other ways to fit the data, e.g., to fit just the rapid dissociation phase (the first 5 s) because slow dissociation phase is more affected by nonspecific binding, to fit without the highest concentrations in which aggregates might exist.…”

Section: Discussionmentioning

confidence: 99%

“…Only peptides with t 1/2 longer than 20 h were selected for further SPR analysis, and this peptide selection allows us to exclude peptide off-rate from D b as an important consideration in analyses that follow. For example, V3A is a poor stimulator for P14 T cells (44). Although V3A/D b complex binds to P14 TCR with high affinity (K D of 2.3 M), V3A does not stabilize D b well (data not shown), so we excluded it for further biological function analysis because the biological activity would be a function of pMHC dissociation and rebinding as well as TCR-pMHC binding.…”

Section: Selection Of Peptides That Stably Bind To D Bmentioning

confidence: 99%

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CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate

Tian

Maile

Collins

et al. 2007

The Journal of Immunology

115

114

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Binding of peptide/MHC (pMHC) complexes by TCR initiates T cell activation. Despite long interest, the exact relationship between the biochemistry of TCR/pMHC interaction (particularly TCR affinity or ligand off-rate) and T cell responses remains unresolved, because the number of complexes examined in each independent system has been too small to draw a definitive conclusion. To test the current models of T cell activation, we have analyzed the interactions between the mouse P14 TCR and a set of altered peptides based on the lymphocytic choriomeningitis virus epitope gp33–41 sequence bound to mouse class I MHC Db. pMHC binding, TCR-binding characteristics, CD8+ T cell cytotoxicity, and IFN-γ production were measured for the peptides. We found affinity correlated well with both cytotoxicity and IFN-γ production. In contrast, no correlation was observed between any kinetic parameter of TCR-pMHC interaction and cytotoxicity or IFN-γ production. This study strongly argues for an affinity threshold model of T cell activation.

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Section: The P14 Tcr-gp33/d B Interaction Features Low Binding Affinisupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Selection Of Peptides That Stably Bind To D Bmentioning

confidence: 99%

See 1 more Smart Citation

CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate

Tian

Maile

Collins

et al. 2007

The Journal of Immunology

115

114

View full text Add to dashboard Cite

show abstract

“…Analysis of the binding kinetics for these two complexes indicates that these exceptionally low affinities were the result of a combination of faster k off values ($0.3 s À1 ) and slower k on values ($700 M À1 .s À1 ) ( Figure 4E, Table 3). The k off values were at the fast end of the range previously reported for syngeneic agonist TCR-peptide-MHC interactions (Boulter et al, 2007;van der Merwe and Davis, 2003) (0.02 < k off < 0.9 s À1 ), whereas the k on values were significantly slower (3000 > k on > 200,000 mol À1 .s À1 ) (van der Merwe and Davis, 2003).…”

Section: Low-affinity Tcr Binding To Microbial Peptides Presented By mentioning

confidence: 88%

T Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides

et al. 2009

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Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS.

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“…The contribution of constitutive Lck activity to CD8+ memory T cell sensitivity may therefore be dependent on the antigen. For example, the virus-specific memory responses induced by gp33-specific TCR-expressing T cells (K D = 3 μM) [68] are independent of Lck activity [67]. Yet responses to lower affinity self-antigens, such as gp100 (K D = 9.3 μM) [69], as described herein, may be Lck-dependent.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets

Moogk

Shi

et al. 2016

The Journal of Immunology

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CD8+ T cells develop increased sensitivity following antigen experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that more than 50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with less than 20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM. Further, we observed superior cytotoxic effector function in TEM compared with TCM, and provide evidence that this results from a lower probability of TCM reaching threshold signaling due to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8+ TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase (Csk), and use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM. Together, this work demonstrates a role for constitutive Lck activity in controlling antigen sensitivity, and suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications.

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Potent T cell agonism mediated by a very rapid TCR/pMHC interaction

Cited by 35 publications

References 30 publications

CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate

CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate

T Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides

Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets

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