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 e...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.展开更多
Complex immune responses have evolved to protect multicellular organisms against the invasion of pathogens.This has exerted strong developmental pressure for specialized functions that can also limit damage to self-ti...Complex immune responses have evolved to protect multicellular organisms against the invasion of pathogens.This has exerted strong developmental pressure for specialized functions that can also limit damage to self-tissue.Two arms of immunity,the innate and adaptive immune systems,have evolved for quick,non-specific immune responses to pathogens and more efficient,long-lasting ones upon specific recognition of recurrent pathogens.Specialized cells have arisen as the sentinels of these functions,including macrophages,natural killer(NK),and T and B-lymphocytes.Interestingly,a population of immune cells that can exert both of these complex functions,NKT cells,not only share common functions but also exhibit shared cell surface markers of cells of both arms of the immune system.These features,in combination with sophisticated maintenance of immune homeostasis,will be dis-cussed.The recent finding of self-peptide reactivity of NKT cells in the context of CD1d,with capacity to regulate multiple auto-immune and inflammatory conditions,motivates the current proposal that self-reactive NKT cells might be the ancestral link between present NK and T cells.Their parallel selection through evolution by higher vertebrates could be related to their central function as master regulators of immune homeostasis that in part is shared with regulatory T cells.Hypothetical views on how self-reactive NKT cells secure such a central role will also be proposed.展开更多
基金This study was supported by funding from the Danish Council For Independent Research(DFF)-Medical Science(DFF-4183–00427B),Danish Multiple Sclerosis Society,and Lundbeck Foundation to S.Issazadeh-Navikas and the MS International Federation-McDonald Fellowship to M.H.
文摘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.
基金supported by grants from the Lundbeck Foundation in Denmark,the Danish Cancer Society,the Danish Research Council-Medicine,and the Novo Nordisk Foundation.
文摘Complex immune responses have evolved to protect multicellular organisms against the invasion of pathogens.This has exerted strong developmental pressure for specialized functions that can also limit damage to self-tissue.Two arms of immunity,the innate and adaptive immune systems,have evolved for quick,non-specific immune responses to pathogens and more efficient,long-lasting ones upon specific recognition of recurrent pathogens.Specialized cells have arisen as the sentinels of these functions,including macrophages,natural killer(NK),and T and B-lymphocytes.Interestingly,a population of immune cells that can exert both of these complex functions,NKT cells,not only share common functions but also exhibit shared cell surface markers of cells of both arms of the immune system.These features,in combination with sophisticated maintenance of immune homeostasis,will be dis-cussed.The recent finding of self-peptide reactivity of NKT cells in the context of CD1d,with capacity to regulate multiple auto-immune and inflammatory conditions,motivates the current proposal that self-reactive NKT cells might be the ancestral link between present NK and T cells.Their parallel selection through evolution by higher vertebrates could be related to their central function as master regulators of immune homeostasis that in part is shared with regulatory T cells.Hypothetical views on how self-reactive NKT cells secure such a central role will also be proposed.
