LIGHT Expression by Mucosal T Cells May Regulate IFN-γ Expression in the Intestine

Abstract

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-γ. LIGHT was induced in memory CD45RO CD4+ T cells and by IFN-γ-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-γ production in lamina propria T cells, while blocking LIGHT inhibited CD2-dependent induction of IFN-γ synthesis, indicating a role for LIGHT in the regulation of IFN-γ 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.

LIGHT Is Constitutively Expressed on T and NK Cells in the Human Gut and Can Be Induced by CD2-Mediated Signaling

“…1A), contrary to cells isolated from enzymatically disrupted tissue, which do not stain for surface LIGHT protein. Cells from the inflamed or uninvolved colon (shown), small bowel, or rectum consistently expressed membrane LIGHT, although expression was not detected in cells from the PB or draining mesenteric lymph nodes whether inflamed or not (11). LIGHT expression diminished over 24 -48 h in culture, but could be rapidly induced to maximal levels by PMA and ionomycin (P/I) activation, in accordance with the induction profile characteristic of LP T cells (Fig.…”

“…LIGHT expression diminished over 24 -48 h in culture, but could be rapidly induced to maximal levels by PMA and ionomycin (P/I) activation, in accordance with the induction profile characteristic of LP T cells (Fig. 1A) (11).…”

“…LIGHT expression has only been detected on in vitro activated intestinal or peripheral blood (PB) T cells (11), but no direct evidence exists for LIGHT expression by gut lymphoid cells in vivo. We developed a mechanical disruption technique for the isolation of lymphocytes from the LP, because traditional enzymatic release of lymphocytes from intestinal tissue may remove cell surface proteins.…”

“…TNF is implicated as an important contributor to intestinal inflammation with a subset of patients with CD responding to anti-TNF therapy (9). However, the partial success of blocking TNF emphasizes the complexity of mucosal immune regulatory mechanisms, prompting an investigation of other TNF-related ligands, such as lymphotoxin (LT) ␣␤ and lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT), in human IBD pathology (2,10,11).…”

Neutralization of LIGHT ameliorates acute dextran sodium sulphate‐induced intestinal inflammation

“…19 LIGHT expression has also been reported to provide costimulatory signals resulting in proliferation and cytokine production and the induction of IFN-c production in peripheral blood as well as lamina propria T cells. 20 Several studies have suggested a role of monocytes and dendritic cells in the onset and severity of IBD. For example, the depletion of monocytes and dendritic cells in DSS-induced experimental colitis resulted in the amelioration of disease symptoms.…”