Abstract Skin‐resident antigen‐presenting cells (APC) play an important role in maintaining peripheral tolerance via immune checkpoint proteins and induction of T regulatory cells (Tregs). However, there is a lack of knowledge on how to expand or recruit immunoregulatory cutaneous cells without causing inflammation. Here, it is shown that administration of a non‐coding single‐stranded oligonucleotide (ssON) leads to CCR2‐dependent accumulation of CD45 + CD11b + Ly6C + cells in the skin that express substantial levels of PD‐L1 and ILT3. Transcriptomic analyses of skin biopsies reveal the upregulation of key immunosuppressive genes after ssON administration. Functionally, the cutaneous CD11b + cells inhibit Th 1/2/9 responses and promote the induction of CD4 + FoxP3 + T‐cells. In addition, ssON treatment of imiquimod‐induced inflammation results in significantly reduced Th 17 responses. It is also shown that induction of IL‐10 production in the presence of cutaneous CD11b + cells isolated after ssON administrations is partly PD‐L1 dependent. Altogether, an immunomodulatory ssON is identified that can be used therapeutically to recruit cutaneous CD11b + cells with the capacity to dampen Th cells.

A Non‐Coding Oligonucleotide Recruits Cutaneous CD11b+ Cells that Inhibit Thelper Responses and Promote Tregs