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

Abstract

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 IFNγ production. Lack of genomic ADAM12 and its knockdown in T cells diminished T-bet and IFNγ 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 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.

Association between single nucleotide variants and severe chronic pain in older adult patients after lower extremity arthroplasty

“…As a costimulatory molecule for T-helper 1 cell activation, ADAM12 mediates tissue in ammation and may play a role in the formation and development of pain. The polymorphism of ADAM12 has also been signi cantly associated with knee OA (Liu et al, 2021;Lv et al, 2017). Many of the genes signi cantly correlated with CPSP in this study are associated with the pathogenesis of arthritis, including BCAP29, IDO2, IGFBP1, TLR10, and TNC.…”

Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance

“…The strong fibroblast-CD8+ T cell interaction reflected increased costimulatory and recruitment integrin communications in ribociclib sensitive tumors at day 180 (e.g. ADAM12-ITGB1:t=4.77, p<0.05) 31,32 . Cancer cells of ribociclib sensitive tumors also provided greater amounts of immune-activating communications to myeloid cells, including stimulation of CCR5/7 receptors 33 (df=6, t= 4.73, p<0.01) (Table S2).…”

Human Lung-resident Mucosal-Associated Invariant T cells are Abundant, Express Antimicrobial Proteins, and are Cytokine Responsive

“…Genes associated with long term survival of T cells including RUNX2 , which plays a T cell intrinsic role in the long-term persistence of memory CD8 + T cells after LCMV infection in mice 35 , LTK, TNFSF13B, IL7R , and TNFSF25 were more highly expressed by MAIT cells. Specific costimulatory receptors were also enriched in MAIT cells including CD40LG and ADAM12 36 . The MAIT cell population differentially expressed the following cytotoxicity related-genes: IL26, GZMK, IL1RI, AMICA1, NCR3, LTB , and SCRN1.…”