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 IFNγproduction.Lack of genomic ADAM12 and its knockdown in T cells diminished T-bet and IFNγproduction 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 of ADAM12 profoundly 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.