Dendritic cell expression of ADAM23 governs T cell proliferation and cytokine production through the α(v)β(3) integrin receptor

Abstract

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.

Dysregulation of adenosine kinase isoforms in breast cancer

“…Thus, This effect might not only occur in breast cancer but also could be a general feature of cells with dysregulated cell cycle. Secondly, metalloprotease and adhesion molecules, MMP9 and ADAM23, are involved in the breakdown of the extracellular matrix in physiological processes such as embryonic development, reproduction, and tissue remodeling [40]; they also play an important role in metastasis of cancer [41]. Studies have shown that a loss of expression of ADAM23 gene and its correlation with promoter methylation has been frequently reported in breast cancer, brain cancer, and pancreatic cancer [42,43].…”

Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

“…With the possibility that Gal-8 may stimulate APC to sustain T cell activation after priming, we investigated whether this lectin displayed a direct effect on DC function. BMDCs, differentiated in vitro from GM-CSF/IL-4 conditioned mice bone marrow cultures, constitute a DC model that has been largely used to study many aspects of APCs [19][20][21][22][23]. Recently, it has been demonstrated that CD11c + BMDC cultures comprise a heterogeneous population of DCs (GM-DC) and macrophages (GM-M) [24].…”

IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells are expanded by dendritic cells silenced for Allograft Inflammatory Factor-1

“…AIF1 was knocked down using an ECM 830 (BTX, Holliston MA) square wave electroporator with 1 nanomole (nmol) of siRNA oligos in 4 mm gap cuvettes in 200 μl of Opti-MEM (Thermo Fisher Scientific) with the following settings: 310 V, 10 ms, 1 pulse. AIF1 siRNA (siAIF1) sequence used: ‘5-GGCAAGAGAUCUGCCAUCUUG-3’ (Thermo Fisher Scientific, Grand Island NY), as previously described [18, 20]. Scrambled siRNA served as controls (siControl): ‘5-GGGCTCTACGCAGGCATTTAA-3’.…”

“…siAIF1 or siControl DC expanded OT-I CD8 + T cells were collected, washed, and plated with target CFSE labeled-CD4 + T cells isolated from WT mice using negative depletion approaches, as previously described [18, 20]. Briefly, the WT CD4 + T cells were split into two equal groups: SIINFEKL peptide-pulsed and scrambled control peptide-pulsed.…”

“…AIF1 siRNA (siAIF1) sequence used: 5 ′ -GGCAAGAGAUCUGCCAUCUUG-3 ′ (Thermo Fisher Scientific), as previously described. 18,20 Scrambled siRNA served as controls (siControl): 5 ′ -GGGCTCTACGCAGGCATTTAA-3 ′ . After electroporation of siRNA on day 5 in CD11c + -sorted DCs, cells were placed back into culture.…”