CD2 expression acts as a quantitative checkpoint for immunological synapse structure and T-cell activation.

Demetriou, P.; Abu-Shah, E.; McCuaig, S.; Mayya, V.; Valvo, S.; Korobchevskaya, K.; Friedrich, M.; Mann, E.; Lee, L. Y.; Starkey, T.; Kutuzov, M. A.; Afrose, J.; Siokis, A.; Oxford IBD Cohort Investigators,; Meyer-Hermann, M.; Depoil, D.; Dustin, M. L.

doi:10.1101/589440

bioRxiv · 10.1101/589440

CD2 expression acts as a quantitative checkpoint for immunological synapse structure and T-cell activation.

Demetriou, P.·Abu-Shah, E.·McCuaig, S.·Mayya, V.·Valvo, S.·Korobchevskaya, K.·Friedrich, M.·Mann, E.·Lee, L. Y.·Starkey, T.·Kutuzov, M. A.·Afrose, J.·Siokis, A.·Oxford IBD Cohort Investigators,·Meyer-Hermann, M.·Depoil, D.·Dustin, M. L.

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Abstract

The CD2 receptor has been described as an adhesion and costimulatory receptor on T cells. Here, transcriptional profiling of colorectal cancers (CRC) revealed a negative correlation between CD2 expression and \"exhausted CD8+ T-cells\" gene signatures. Furthermore, we detected reduced surface CD2 levels in exhausted CD127lowPD-1hi CD3+CD8+ tumour infiltrating lymphocytes (TILs) in CRC. We describe a CD2 expression-level-dependent switch in CD2-CD58 localization between central and peripheral domains in the immunological synapse (IS). A peripheral \"CD2 corolla\" formed when CD2 surface expression was sufficiently high and its cytoplasmic domain intact. The corolla recruited other ligated receptors like CD28, boosted recruitment of activated Src-family kinases (pSrc), LAT and PLC-{gamma} in the IS and consequently T-cell activation in response to a tumour antigen. Corolla formation and pSrc in the IS increased linearly with CD2 expression, whereas pSrc signals were reduced by high, \"exhausted-like\" levels of PD-1, which invaded the corolla. These results suggest two levels of inhibition of Src-family kinases in CD3+CD8+ TILs: reduced CD2 expression and high PD-1 expression.

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Demetriou, P., Abu-Shah, E., McCuaig, S., Mayya, V., Valvo, S., Korobchevskaya, K., Friedrich, M., Mann, E., Lee, L. Y., Starkey, T., Kutuzov, M. A., Afrose, J., Siokis, A., Oxford IBD Cohort Investigators,, Meyer-Hermann, M., Depoil, D., Dustin, M. L.. 2019-03-29. CD2 expression acts as a quantitative checkpoint for immunological synapse structure and T-cell activation.. https://doi.org/10.1101/589440

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