Induced reactivity of intestinal CD4(+) T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation.
Inflammatory bowel disease is an immune-mediated intestinal inflammatory condition that is associated with an increase in autoantibodies that bind to epithelial cells. However, it is unknown whether the epithelial cell-derived products that are recognized by such autoantibodies are involved in the pathogenic process. Through a combined antigen-screening approach utilizing humoral and cellular immune responses, we identify herein an epithelial lectin, galectin-4, that specifically stimulates IL-6 production by CD4(+) T cells. Interestingly, the reactivity of CD4(+) T cells to galectin-4 is precisely elicited under intestinal inflammatory conditions. The galectin-4-mediated production of IL-6 is MHC class II independent and induced by PKCtheta-associated pathway through the immunological synapse. The galectin-4-mediated stimulation of CD4(+) T cells is shown to exacerbate chronic colitis and delay the recovery from acute intestinal injury. These studies identify the presence of an immunogenic, endogenous lectin in the intestine and dissect the biological role of lectin/CD4(+) T cell interactions under inflammatory conditions.
Hokama
Akira
A
Department of Pathology, Massachussets General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Mizoguchi
Emiko
E
Sugimoto
Ken
K
Shimomura
Yasuyo
Y
Tanaka
Yosuke
Y
Yoshida
Masaru
M
Rietdijk
Svend T
ST
de Jong
Ype P
YP
Snapper
Scott B
SB
Terhorst
Cox
C
Blumberg
Richard S
RS
Mizoguchi
Atsushi
A
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D037541:Galectin 4 / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000378:metabolism; D015854:Up-Regulation
D037541:Galectin 4; D015850:Interleukin-6; D011493:Protein Kinase C