Dendritic cell expression of ADAM23 governs T cell proliferation and cytokine production through the α(v)β(3) integrin receptor.
ADAM23 is a member of the brain macrophage-derived chemokine family. Structural homology of ADAM proteins suggests their function as integrin receptors. Previous studies have linked ADAM23 as a dominant contributor to brain development and cancer metastasis. The present studies now show that ADAM23 expression on DCs partially governs antigen-presentation capacities to responder CD4+T cells. With the use of RNAi approaches, knockdown of ADAM23 in murine BMDCs resulted in impaired T cell activation, proliferation, and cytokine production. Knockdown did not alter the maturation profile of DCs (i.e., costimulatory molecule expression or production of proinflammatory cytokines) but markedly impaired cognate T cell responses. There was a significant decrease in antigen-specific clonal expansion coupled with a global decrease in Th cytokine production. Impaired early activation and proliferation did not alter/skew the balance of Th polarization but significantly depressed total levels of IL-2, IFN-γ, IL-4, and IL-17 cytokine production in CD4+T cells primed by ADAM23 knockdown versus control DCs. Finally, neutralizing antibodies targeting the α(v)β(3) integrin receptors resulted in similar phenotypes of impaired CD4+T cell responses. Taken together, these studies show a novel role of ADAM23 in governing DC antigen presentation to cognate CD4+T cells.
Department of Biology, Howard University, Washington, DC, USA.
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Elizondo
Department of Biology, Howard University, Washington, DC, USA.
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Andargie
Department of Biology, Howard University, Washington, DC, USA.
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Marshall
Department of Biology, Howard University, Washington, DC, USA.
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Zariwala
Department of Biology, Howard University, Washington, DC, USA michael.lipscomb@howard.edu.
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Lipscomb
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D055785:Gene Knockdown Techniques; D039302:Integrin alphaVbeta3 / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
D057134:Antibodies, Neutralizing; D016207:Cytokines; D039302:Integrin alphaVbeta3; D009419:Nerve Tissue Proteins; C111390:OVA 323-339; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D010047:Ovalbumin; D051722:ADAM Proteins; C121259:Adam23 protein, mouse
adhesion; antigen presentation; costimulation; cytoskeleton; disintegrin