CD2 costimulation strength: A key regulator of T cell function and anti-tumor immunity that is epigenetically regulated

CD2 is a key costimulatory receptor on human T cells, but its surface abundance regulation and its functional significance remain incompletely defined. We found that CD2 expression is markedly reduced in CD4⁺ and CD8⁺ tumor-infiltrating T cells from human brain tumors. To identify factors sustaining CD2 expression, we performed a genome-wide CRISPR-Cas9 screen in Jurkat T cells and discovered BAP1 and SUZ12 as regulators. Loss of BAP1 caused downregulation of CD2, TRAC, and other costimulatory receptors, with CD2 and TRAC expression remaining impaired even after activation. Transcriptomic analysis linked BAP1 deficiency to the disruption of programs controlling T cell identity and differentiation, while histone deacetylase inhibition partially restored CD2. In primary human T cells, reduced CD2 costimulation impaired the magnitude of proliferation and IFN-γ production. These findings identify BAP1 as a central regulator of receptor expression and highlight CD2 as a tunable modulator of human T cell responses.