ADAM12 is a costimulatory molecule that determines Th1 cell fate and mediates tissue inflammation

A disintegrin and metalloproteinase (ADAM)12 was previously found to be expressed in T cells in the inflamed brain. However, the function of ADAM12 in T-cell responses in general and in tissue inflammation has not been examined. Here, we studied the role of ADAM12 in T-cell responses, fate determination on activation, and its functions in T cells to mediate tissue inflammation. We identified ADAM12 as a costimulatory molecule that is expressed on naive T cells and downregulated on stimulation. ADAM12 mimics CD28 costimulatory signaling to activate and induce the proliferation of T-helper 1 (Th1) cells. Monoclonal ADAM12 Fab antibodies trigger T-cell activation by amplifying TCR signaling to stimulate T-bet-mediated IFN gamma production. Lack of genomicADAM12and its knockdown in T cells diminished T-bet and IFN gamma production in Th1 cells, whereas other T cells, including Th17 cells, were unaffected. ADAM12 had similar functions in vivo on myelin antigen (MOG(35-55))-induced T-cell activation. We found that genetic loss ofADAM12profoundly alleviated Th1-mediated neuroinflammation and thus disease severity in experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Transcriptomic profiling of MOG(35-55)-specific ADAM12(-/-)T cells revealed differentially expressed genes that are important for T-cell activation, proliferation, and costimulatory signaling and Th1 pathogenicity, consistent with their inability to cause T-cell-mediated skin inflammation in a model of adoptive delayed-type hypersensitivity. We conclude that ADAM12 is a T-cell costimulatory molecule that contributes to the pathogenesis of tissue inflammation and a potential target for the treatment of Th1-mediated diseases.

Automated summary

ADAM12 is identified as a costimulatory molecule in T cells that mimics CD28 signaling to activate and induce proliferation of Th1 cells. Lack of genomic ADAM12 in T cells diminishes T-bet and IFN gamma production in Th1 cells, providing a potential target for the treatment of Th1-mediated diseases.