TY - JOUR
T1 - Integrin Subunit CD18 Is the T-Lymphocyte Receptor for the Helicobacter pylori Vacuolating Cytotoxin
AU - Sewald, Xaver
AU - Gebert-Vogl, Bettina
AU - Prassl, Sandra
AU - Barwig, Iris
AU - Weiss, Evelyn
AU - Fabbri, Monica
AU - Osicka, Radim
AU - Schiemann, Matthias
AU - Busch, Dirk H.
AU - Semmrich, Monika
AU - Holzmann, Bernhard
AU - Sebo, Peter
AU - Haas, Rainer
PY - 2008/1/17
Y1 - 2008/1/17
N2 - Helicobacter pylori infection is associated with gastritis, ulcerations, and gastric adenocarcinoma. H. pylori secretes the vacuolating cytotoxin (VacA), a major pathogenicity factor. VacA has immunosuppressive effects, inhibiting interleukin-2 (IL-2) secretion by interference with the T cell receptor/IL-2 signaling pathway at the level of calcineurin, the Ca2+-calmodulin-dependent phosphatase. Here, we show that VacA efficiently enters activated, migrating primary human T lymphocytes by binding to the β2 (CD18) integrin receptor subunit and exploiting the recycling of lymphocyte function-associated antigen (LFA)-1. LFA-1-deficient Jurkat T cells were resistant to vacuolation and IL-2 modulation, and genetic complementation restored sensitivity to VacA. VacA targeted human, but not murine, CD18 for cell entry, consistent with the species-specific adaptation of H. pylori. Furthermore, expression of human integrin receptors (LFA-1 or Mac-1) in murine T cells resulted in VacA-mediated cellular vacuolation. Thus, H. pylori co-opts CD18 as a VacA receptor on human T lymphocytes to subvert the host immune response.
AB - Helicobacter pylori infection is associated with gastritis, ulcerations, and gastric adenocarcinoma. H. pylori secretes the vacuolating cytotoxin (VacA), a major pathogenicity factor. VacA has immunosuppressive effects, inhibiting interleukin-2 (IL-2) secretion by interference with the T cell receptor/IL-2 signaling pathway at the level of calcineurin, the Ca2+-calmodulin-dependent phosphatase. Here, we show that VacA efficiently enters activated, migrating primary human T lymphocytes by binding to the β2 (CD18) integrin receptor subunit and exploiting the recycling of lymphocyte function-associated antigen (LFA)-1. LFA-1-deficient Jurkat T cells were resistant to vacuolation and IL-2 modulation, and genetic complementation restored sensitivity to VacA. VacA targeted human, but not murine, CD18 for cell entry, consistent with the species-specific adaptation of H. pylori. Furthermore, expression of human integrin receptors (LFA-1 or Mac-1) in murine T cells resulted in VacA-mediated cellular vacuolation. Thus, H. pylori co-opts CD18 as a VacA receptor on human T lymphocytes to subvert the host immune response.
KW - CELLBIO
KW - MICROBIO
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=38049042859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38049042859&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2007.11.003
DO - 10.1016/j.chom.2007.11.003
M3 - Article
C2 - 18191791
AN - SCOPUS:38049042859
SN - 1931-3128
VL - 3
SP - 20
EP - 29
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -