Activation of beta(1) integrins mediates proliferation and inhibits apoptosis of intestinal CD4-positive lymphocytes.
A characteristic of lamina propria lymphocytes (LPL) is their low proliferative response to stimuli of the CD3 pathway. beta(1) integrins were expressed on LPL; however, their function is unknown. Therefore, we determined whether beta(1) integrins contribute to T cell responses by providing costimulatory signals. Integrins on CD4(+) LPL of controls and patients with inflammatory bowel disease were characterized by flow cytometry. Cells were stimulated by anti-CD3 or anti-CD2 antibodies either alone or in combination with a stimulatory beta(1) integrin antibody (12G10). Proliferation and apoptosis were measured by [(3)H]thymidine pulsing or flow cytometry. Cytokine mRNA and apoptosis-related transcripts were quantified by reverse transcriptase-PCR. We demonstrated that beta(1) integrin costimulation restored CD3-induced proliferation of CD4(+) LPL and reduced activation-induced apoptosis. Activation of beta(1) integrins by addition of 12G10 antibody to CD3-stimulated cells restored their capacity to express proinflammatory cytokine transcripts. Further, expression of the activated form of beta(1) integrins was significantly elevated on LPL from inflamed mucosa. These studies demonstrate that beta(1) integrin costimulation modulates the response of LPL after TCR stimulation. An increased expression of activated beta(1) integrins on LPL in intestinal inflammation may abolish their unresponsiveness to antigens and perpetuate the inflammatory process.
Stallmach
A
A
Institute of Immunology of University of Heidelberg, Heidelberg, Germany. inasta@med-rz.uni-sb.de
Giese
T
T
Pfister
K
K
Wittig
B M
BM
Künne
S
S
Humphries
M
M
Zeitz
M
M
Meuer
S C
SC
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000911:Antibodies, Monoclonal; C494811:BCL2L1 protein, human; D017252:CD3 Complex; D019012:Integrin beta1; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D007371:Interferon-gamma