LIGHT expression by mucosal T cells may regulate IFN-gamma expression in the intestine.
The TNF superfamily of cytokines play an important role in T cell activation and inflammation. Sustained expression of lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT) (TNFSF14) causes a pathological intestinal inflammation when constitutively expressed by mouse T cells. In this study, we characterized LIGHT expression on activated human T cell subsets in vitro and demonstrated a direct proinflammatory effect on regulation of IFN-gamma. LIGHT was induced in memory CD45RO CD4+ T cells and by IFN-gamma-producing CD4+ T cells. Kinetic analysis indicated rapid induction of LIGHT by human lamina propria T cells, reaching maximal levels by 2-6 h, whereas peripheral blood or lymph node-derived T cells required 24 h. Further analysis of intestinal specimens from a 41 patient cohort by flow cytometry indicated membrane LIGHT induction to higher peak levels in lamina propria T cells from the small bowel or rectum but not colon, when compared with lymph node or peripheral blood. Independent stimulation of the LIGHT receptor, herpesvirus entry mediator, induced IFN-gamma production in lamina propria T cells, while blocking LIGHT inhibited CD2-dependent induction of IFN-gamma synthesis, indicating a role for LIGHT in the regulation of IFN-gamma and as a putative mediator of proinflammatory T-T interactions in the intestinal mucosa. Taken together, these findings suggest LIGHT-herpesvirus entry mediator mediated signaling as an important immune regulatory mechanism in mucosal inflammatory responses.
Cohavy
Offer
O
Cedars-Sinai Inflammatory Bowel Disease Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Zhou
Jaclyn
J
Granger
Steve W
SW
Ware
Carl F
CF
Targan
Stephan R
SR
D000328:Adult; D018801:CD2 Antigens / Q000502:physiology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007422:Intestines / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D018801:CD2 Antigens; D008565:Membrane Proteins; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens