Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin.
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 beta2 (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.
Sewald
Xaver
X
Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, Pettenkoferstrasse 9a, D-80336 Munich, Germany.
Gebert-Vogl
Bettina
B
Prassl
Sandra
S
Barwig
Iris
I
Weiss
Evelyn
E
Fabbri
Monica
M
Osicka
Radim
R
Schiemann
Matthias
M
Busch
Dirk H
DH
Semmrich
Monika
M
Holzmann
Bernhard
B
Sebo
Peter
P
Haas
Rainer
R
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology
D001426:Bacterial Proteins; D018821:CD18 Antigens; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D011948:Receptors, Antigen, T-Cell; C074689:VacA protein, Helicobacter pylori