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 (MOG35–55)-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 MOG35–55-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.
Highlights
T lymphocytes are central in exerting the proper immune responses against microbial infections and during cancer progression
ADAM12 on T cells is downregulated on activation ADAM12 has only been reported at the mRNA level in T cells.[11,14]
We assessed whether ADAM12 could be detected at the protein level on T cells, examining spleens from naive and myelin oligodendrocyte glycoprotein (MOG)35–55-immunized mice by flow cytometry
Summary
T lymphocytes are central in exerting the proper immune responses against microbial infections and during cancer progression. Cell receptor (TCR) and costimulatory signaling is essential to mount suitable immune responses. Several transmembrane cluster of differentiation (CD) molecules, such as CD4, CD8, CD3, and CD7, are required for or contribute to TCR signaling. A prerequisite of effective T-cell activation is the capacity of T cells to establish close contact or synapses with antigen-presenting cells (APCs).[1] To this end, ligands or receptors that are commonly referred to as costimulatory molecules on T cells, such as CD28, bind to CD80 or CD86 (B7.1/2) molecules on APCs and stimulate additional intracellular signaling, leading to complete T-cell activation.[1] Whereas certain costimulatory interactions, such as CD28-B7s and CD40-CD40L, contribute to T-cell activation,[2] others, such as CTLA-4-B7s and PD-1-PD-L1, result in negative signaling that terminates T-cell activation.[3]
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