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A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals


An Author Correction to this article was published on 29 October 2020

This article has been updated


The CD2–CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a ‘CD2 corolla’. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2–CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2–CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8+ tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.

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Fig. 1: A unique ring pattern, called corolla, formed by CD2–CD58 interactions in the IS.
Fig. 2: The corolla organizes multiple co-stimulatory receptor interactions.
Fig. 3: CD2 corolla boosts CD2-dependent TCR-signal amplification.
Fig. 4: Regulation of signaling in the corolla by PD-1 engagement.
Fig. 5: Number of CD2 per human T cell predicts CD58 engagement and corolla formation.
Fig. 6: CD2 expression determines corolla formation independent of signaling.
Fig. 7: CD8+ TILs from people with cancer can express considerably low levels of CD2.

Data availability

scRNA-seq data are available in Supplementary Table 7 in the NCBI Gene Expression Omnibus single-cell-sequencing data section. Additional data and information that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

No custom code or mathematical algorithm was used when acquiring or analyzing data included in this study.

Change history

  • 29 October 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


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We thank S. Davis, P.A. Van Der Merwe, O. Dushek and R. Owens (University of Oxford) for kindly providing plasmids and HLA-A2 pMHC monomers. We also thank M. Dumoux (The Rosalind Franklin Institute) for kindly providing plasmids. We thank M. H. Brown and S. Sivakumar for helpful discussion and feedback on experiments and writing of the manuscript, and all the Dustin lab members for their kind support. We thank S. Balint for his help on some experiments and for maintaining the TIRF microscope, C. Laggerholm for access to and assistance with the Airyscan confocal microscope and P. Cespedes for his contribution in methods development for quantification of surface molecules on T cells. The results published here are in part based upon data generated by the TCGA Research Network: A Kennedy Trust for Rheumatology (KTRR) Prize Studentship supported P.D. An UCB-Oxford Post-doctoral Fellowship supported E.A.S. A grant from The Research Council of Norway in conjunction with Marie Sklodowska-Curie Actions (275466) supported A.K. Wellcome Trust Principal Research Fellowship 100262Z/12/Z, and a grant from KTRR supported M.L.D. KTRR supports the Kennedy Institute Microscopy Facility and the Wolfson Foundation supports the Weatherall Institute Microscopy Facility. A collaborative grant from the Human Frontiers Science Program supported E.A.-S., A.S. and M.M.-H. A.S. was supported by the German Research Foundation (DFG) and Collaborative Research Center (SFB 854) ‘Molecular Organization of Cellular Communication within the Immune System’. A fellowship from Philippe Foundation partially supported D.D. A Wellcome Trust Senior Research Fellowship 207537/Z/17/Z supported E.A.-S. and M.A.K. NIHR Biomedical Research Centre, Oxford, supports the Oxford Gastro-Intestinal Biobank and the Oxford Inflammatory Bowel Disease Cohort study. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. We acknowledge the contribution to this study made by the Oxford Centre for Histopathology Research and the Oxford Radcliffe Biobank, which are supported by the NIHR Oxford Biomedical Research Centre.

Author information





P.D. conceptualized the project, designed and performed experiments, analyzed the data and co-wrote the manuscript. E.A.-S. designed, performed and analyzed experiments and co-wrote the manuscript. S.V. prepared and performed experiments and maintained critical infrastructure. K.K. assisted in confocal micrsocpy experiments and acquiring confocal microscopy images. A.K. performed and analyzed experiments. S.M., M.F. and E.M. prepared single-cell suspensions from CRC tissue. E.A.-S. prepared single-cell suspensions from EndoC and OC samples. S.M. performed transcriptional analysis. P.D. and E.A.S. performed the staining and acquisition experiments of CRC tissues. E.A.S. performed the staining and acquisition experiments of EndoC and OC tissues. J.A., H.R., S.Y., S.V., V.M. and M.A.K. prepared essential reagents for experiments. V.M. designed image-analysis software and trained P.D. in its use. L.Y.W.L. and T.S. performed transcriptional analysis of CRC, HCC, NSCLC and melanoma cohorts. The Oxford IBD Cohort Investigators provided access to CRC tissue and clinical data. M.M. provided EndoC and OC samples and clinical data and contributed to discussion of patient data. N.W. and A.A.A. provided access to Endo and OC samples. P.D., E.A.S., V.M., D.D., A.S., M.M.-H. and M.L.D. made intellectual contributions to the project through regular discussions. D.D. provided training to P.D. and conceptualized and designed experiments. M.L.D. supervised the research and facilitated collaboration. P.D. drafted the manuscript, and E.A.-S., V.M., S.M., D.D. and M.L.D. contributed to writing and editing.

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Correspondence to Michael L. Dustin.

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Supplementary information

Supplementary Information

Suppplementary Figs. 1–6.

Reporting Summary

Supplementary Video 1

Tracking of IS formation by a human T cell incubated on SLBs reconstituted with ICAM-1 (200 molecules per μm2), anti-CD3 Fab (30 molecules per μm2) or CD58 (200 molecules per μm2). Cells were imaged at 4-s intervals with TIRFM. Scale bar, 5 μm.

Supplementary Video 2

Tracking of IS formation by a human T cell incubated on SLBs reconstituted with ICAM-1 (200 molecules per μm2), anti-CD3 Fab (30 molecules per μm2) or CD58 (200 molecules per μm2). Cells were imaged at 4-s intervals with TIRFM. Scale bar, 5 μm.

Supplementary Video 3

Tracking of IS formation by a human T cell incubated on SLBs reconstituted with ICAM-1 (200 molecules per μm2), anti-CD3 Fab (30 molecules per μm2), CD58 (200 molecules per μm2) or CD80 (100 molecules per μm2). Cells were imaged at 4-s intervals with TIRFM.

Supplementary Tables

Tables supporting main data presented in the manuscript.

Supplementary Data

Numerical data used for plotting Supplementary Figs. 3–6.

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Source Data Fig. 4

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Demetriou, P., Abu-Shah, E., Valvo, S. et al. A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals. Nat Immunol 21, 1232–1243 (2020).

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