Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen‐specific regulatory T cells, and suppresses experimental inflammatory arthritis

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK‐dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen‐specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor β, a process required for suppression of T cell responses and differentiation of antigen‐specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen‐dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen‐specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte–derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination.</jats:p></jats:sec>