Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions.

Abstract

The functional properties of intraepithelial lymphocytes (IEL) in normal human jejunum, ileum, and colon were investigated. Cytokine mRNA expression in IEL and enterocytes was determined by reverse transcriptase-PCR and IFN-gamma+ IEL by immunohistochemistry. Polyclonal activators were used to study proliferation and IFN-gamma secretion of IEL, and an anti-CD3-mediated redirected cytotoxicity assay was used to determine the lytic potential of IEL. Freshly isolated IEL at all three gut levels expressed mRNA for IL-1 beta, IL-2, IL-8, IFN-gamma, and TNF-alpha. Approximately 10% of IEL produced IFN-gamma, suggesting that IEL are immunologically active in vivo, performing similar functions along the intestine. IEL could be stimulated further in vitro to express IL-10, TNF-beta, and TGF-beta 1, while no Th2-type cytokines were induced, suggesting suppressive and cytolytic functions for IEL. All three jejunal IEL subpopulations (CD4-CD8-TCR-gamma delta+, CD4+TCR-alpha beta+, CD8+TCR-alpha beta+) expressed the same four cytokines, IL-2, IL-8, IFN-gamma, and TNF-alpha, indicating that CD4+TCR-alpha beta+ IEL are Th1 cells and that TCR-gamma delta+ IEL and CD8+TCR-alpha beta+ IEL include cytotoxic effector cells. Indeed, freshly isolated jejunal IEL displayed cytolytic activity. IEL were induced to proliferation by anti-CD3/TCR complex mAbs and leukoagglutinin, but not by Con A. There was no correlation between the magnitude of the proliferative response and the amounts of secreted IFN-gamma. Enterocytes expressed IL-1 beta and IL-8, and sometimes TNF-alpha. Although jejunal enterocytes express HLA-DR and hsp60, Ag presentation by these cells may induce anergy since their cytokine profile is different from that of classical APCs.

Cytokine Expression in Rat Colon During Postnatal Development

“…Previous studies also detected TNF‐α gene expression in the healthy colonic epithelium (17,18,56), in colon carcinoma cell lines (16,17) or in the epithelium and fibroblasts after the onset of inflammation (19,47,57). The postnatal developmental profile of TNF‐α gene expression is similar to that of IL‐1β with no changes in the proximal colon and a progressive decrease in the distal part of the colon.…”

“…We show here that, like in the small intestine (20), the proinflammatory cytokine IL‐1β mRNA is expressed in the colonic mucosa during the weaning period and in the adult animal. This RT‐PCR analysis also allowed the detection of IL‐1β mRNA in the cultured IEC‐18 cells, such as in enterocytes isolated from the healthy human intestine (17). However, unlike these results, IL‐1β has previously been localised in epithelial cells only in pathological conditions such as intestinal inflammation (46,47) or cancer (16).…”

“…Intestinal proinflammatory cytokines (tumor necrosis factor-> [TNF->] and interleukin-1A [IL-1A]) play a critical role in mucosal defense and intestinal homeostasis. In addition to lamina propria immune cells, TNF-> and IL-1A are constitutively expressed in epithelial cell lines derived from colon carcinoma (T84, HT29 and Caco-2 [16]), colonic epithelial cells (17,18), intraepithelial lymphocytes and subepithelial myofibroblasts (19,20). Besides their proinflammatory function, TNF-> and IL-1A regulate diverse biological functions and are mainly involved in tissue repair promoting migration of epithelial cells, deposition of extracellular matrix proteins (19) and proliferation of epithelial (4,21) and mesenchymal cells (22,23).…”

Changes in Extrathymic T Cells in the Liver and Intestinal Intraepithelium in Mice with Obstructive Jaundice

“…It is also possible that cytokines from bile or IELs may influence the change in lymphocyte proportions. Lundqvist et al noted that the ETCs in the IE maintain the barrier function through the production of cytokines, such as interleukin‐2 or interferon‐γ (IFNγ), from the IELs themselves [29]. Moreover, the small amount of tumor necrosis factor or IFNγ detectable in bile may influence this change [22].…”

The Enteropathy of Celiac Disease

“…Interestingly, TcR␥␦ IELs recognize MICA and MICB antigens, which are stress-induced MHC molecules on intestinal epithelial cells (35). Activated IELs can produce a number of cytokines including IFN-␥, IL-2, IL-8 and tumor necrosis factor ␣, and have cytotoxic functions (36). In celiac disease, but not in giardiasis, IELs stain positive for markers of cytotoxicity, such as granzyme B and TiA (37), and a selective expansion has been recently demonstrated of an IEL population expressing CD94, the HLA-E-specific natural killer receptor that may be related to TcR activation or IL-15 secretion (38).…”