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