ADAM-15/metargidin mediates homotypic aggregation of human T lymphocytes and heterotypic interactions of T lymphocytes with intestinal epithelial cells.
Intestinal epithelial cells (IEC) play an immunoregulatory role in the intestine. This role involves cell-cell interactions with intraepithelial lymphocytes that may also play a role in some enteropathies. The discovery of the RGD motif-containing Protein ADAM-15 (a disintegrin and metalloprotease-15) raises the question of its involvement in these cell-cell interactions. Cell adhesion assays were performed using the Jurkat E6.1 T cell line as a model of T lymphocytes and Caco2-BBE monolayers as a model of intestinal epithelia. Our results show that an anti-ADAM-15 ectodomain antibody inhibited the attachment of Jurkat cells on Caco2-BBE monolayers. Overexpression of ADAM-15 in Caco2-BBE cells enhanced Jurkat cell binding, and overexpression of ADAM-15 in Jurkat cells enhanced their aggregation. Mutagenesis experiments showed that both the mutation of ADAM-15 RGD domain or the deletion of its cytoplasmic tail decreased these cell-cell interactions. Moreover, wound-healing experiments showed that epithelial ADAM-15-mediated Jurkat cell adhesion to Caco2-BBE cells enhances the mechanisms of wound repair. We also found that ADAM-15-mediated aggregation of Jurkat cells increases the expression of tumor necrosis factor-alpha mRNA. These results demonstrate the following: 1) ADAM-15 is involved in heterotypic adhesion of intraepithelial lymphocytes to IEC as well as in homotypic aggregation of T cells; 2) both the RGD motif and the cytoplasmic tail of ADAM-15 are involved for these cell-cell interactions; and 3) ADAM-15-mediated cell-cell interactions are involved in mechanisms of epithelial restitution and production of pro-inflammatory mediators. Altogether these findings point to ADAM-15 as a possible therapeutic target for prevention of inappropriate T cell activation involved in some pathologies.
Charrier
Laetitia
L
Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA. lcharri@emory.edu
Yan
Yutao
Y
Nguyen
Hang Thi Thu
HT
Dalmasso
Guillaume
G
Laboisse
Christian L
CL
Gewirtz
Andrew T
AT
Sitaraman
Shanthi V
SV
Merlin
Didier
D
D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D018938:Caco-2 Cells; D002448:Cell Adhesion; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology*; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D014945:Wound Healing
D017931:DNA Primers; D008565:Membrane Proteins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D051722:ADAM Proteins; C098660:ADAM15 protein, human