CD2 expression is co-regulated with stemness- and exhaustion-associated factors in human T cells
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The CD2-CD58 pathway has been highlighted as a major player in anti-tumour T cell immunity. Our study reveals that the strength of CD2 costimulation significantly affects T cell activation, the average number of cell divisions, fold expansion, and IFN-γ production. Notably, proliferation parameters correlate positively with CD25 expression, suggesting a mechanism by which CD2 strength enhances T cell proliferation. We find that human brain cancer tumour-infiltrating CD8+ and CD4+ T cells exhibit reduced levels of CD2, suggestive of a compromised CD2-signal strength in these cells. Through a genome-wide CRISPR-Cas9 knockout screen, we identified two epigenetic regulators, SUZ12 and BAP1, as positive modulators of CD2 expression. BAP1 is crucial for the upregulation and sustained high expression of CD2 following T cell activation. Our findings indicate also that CD2 is co-regulated with other co-stimulatory and inhibitory receptors, as well as factors related to T cell stemness, exhaustion, and metabolism, in a dose-dependent manner. Importantly, we demonstrate that the loss of CD2 due to BAP1 knockout can be rescued by pharmacological inhibition of histone deacetylases. These insights enhance our understanding of CD2-mediated T cell regulation, identify regulators of this pathway and potential therapeutic targets within it.
