A genome-wide CRISPR screening identifies targets that drive tolerogenic dendritic cells.

UBE2L6 is linked to tolerogenic dendritic cell states by regulating CD86 expression through an ISG15–USP18-associated pathway, enabling genome-wide target discovery.

• Why it matters: Key molecular pathways that drive tolerogenic dendritic cell differentiation and phenotype are still unclear, limiting rational development of tolerance-based therapies.
• What they did: The study used CD86 downregulation as a readout, then ran a genome-wide CRISPR-Cas9 knockout screen and followed genes tied to TolDC phenotypes, including CD86 function.
• The result: CD86 is functionally required for TolDC-mediated suppression of T cell proliferation and cytokine secretion, and UBE2L6 is positioned as a regulator of CD86 via an ISG15–USP18-associated pathway.

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