Two-Stage Cooperative T Cell Receptor-Peptide Major Histocompatibility Complex-CD8 Trimolecular Interactions Amplify Antigen Discrimination

Jiang, Ning; Huang, Jun; Edwards, Lindsay J.; Liu, Baoyu; Zhang, Yan; Beal, Cara; Evavold, Brian D.; Zhu, Cheng

doi:10.1016/j.immuni.2010.12.017

Cited by 186 publications

(297 citation statements)

References 54 publications

Supporting

Mentioning

264

Contrasting

Unclassified

Order By: Relevance

“…To determine the bond composition, we calculated the average numbers of Thy-1-a 5 b 1 or Thy-1-Syn4 bimolecular bonds (/n a5b1 S or /n Syn4 S) from the respective adhesion frequencies measured when Syn4 or a 5 b 1 was knocked down, respectively, and compared their sum with the average number of total bonds (/n total S) from the adhesion frequency measured with no treatments (Methods, equation (1)) 53 . Remarkably, the sum of the two bimolecular bond average numbers, /n a5b1 S ¼ 0.173±0.032 and /n Syn4 S ¼ 0.054±0.018, was only 0.227 ± 0.032, significantly smaller than the average number of total bonds, /n total S ¼ 0.341±0.062 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Fiore

Chen

et al. 2014

Nat Commun

Self Cite

View full text Add to dashboard Cite

Cancer cell adhesion to the vascular endothelium is a critical step of tumour metastasis. Endothelial surface molecule Thy-1 (CD90) is implicated in the metastatic process through its interactions with integrins and syndecans. However, how Thy-1 supports cell-cell adhesion in a dynamic mechanical environment is not known. Here we show that Thy-1 supports b 1 integrin-and syndecan-4 (Syn4)-mediated contractility-dependent mechanosignalling of melanoma cells. At the single-molecule level, Thy-1 is capable of independently binding a 5 b 1 integrin and syndecan-4 (Syn4) receptors. However, in the presence of both a 5 b 1 and Syn4, the two receptors bind cooperatively to Thy-1, to form a trimolecular complex. This trimolecular complex displays a unique phenomenon we coin 'dynamic catch', characterized by abrupt bond stiffening followed by the formation of catch bonds, where force prolongs the bond lifetime. Thus, we reveal a new class of trimolecular interactions where force strengthens the synergistic binding of two co-receptors and modulates downstream mechanosignalling.

show abstract

Section: Resultsmentioning

confidence: 99%

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Fiore

Chen

et al. 2014

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…The combined contribution is supported by the observation that the low-affinity TCR L2G2 showed the highest avidity and functional activity in our system. Previous studies (16,41) indicate that the contribution of CD8 to TCR/pMHC interaction is dependent on ligand C B A affinity. However, it is unknown whether the properties of TCRs can determine the magnitude of CD8 contribution (29).…”

Section: Discussionmentioning

confidence: 98%

“…However, it is unknown whether the properties of TCRs can determine the magnitude of CD8 contribution (29). It has been demonstrated that CD8 engages in the TCR/pMHC interaction in the second stage after the TCR/pMHC complex is formed (41). Previous studies were not able to look into this phenomena; however, here, by using seven unique TCRs, we show that the CD8 contribution to TCR/pMHC interaction might be dependent on individual TCRs, because we have clearly demonstrated that CD8 stabilizes L2G2/pMHC interaction more profoundly than any of the other TCRs.…”

Section: Discussionmentioning

confidence: 99%

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

Shi

Malecek

Johnson

et al. 2013

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

202

215

View full text Add to dashboard Cite

T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo , we used a unique self-antigen system comprising seven human melanoma gp100(209–217)-specific TCRs spanning physiological affinities (1–100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-generated high-affinity TCRs do not necessarily improve efficacy.

show abstract

“…intercellular) of TCR-MHC-peptide interactions have indicated binding parameters that were strikingly different from those measured in three-dimensional (e.g. SPR) binding studies (35)(36)(37). This casted doubt on the value of the latter in terms of predicting T cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…This casted doubt on the value of the latter in terms of predicting T cell activation. This is especially intriguing for CD8ϩ T cells, because CD8 can bind to TCR-associated cognate as well as to noncognate MHC-peptide complexes and thereby substantially affect TCR-MHC-peptide binding and T cell activation (12,27,36). The here described assay (Fig.…”

Section: Discussionmentioning

confidence: 99%