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 9exhausted CD8 + T-cells9 gene signatures. Furthermore, we detected reduced surface CD2 levels in exhausted CD127 low PD-1 hi 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 9CD2 corolla9 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-γ 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, 9exhausted-like9 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.