Regulation of cell death and survival in intestinal intraepithelial lymphocytes

Brunner, Thomas; Arnold, Diana; Wasem, Christoph; Herren, Simon; Frutschi, Corina

doi:10.1038/sj.cdd.4400854

Cited by 47 publications

(36 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro exposure to GCs induces thymocyte apoptosis (18,26), and blocking GC receptors, inhibiting GC biosynthesis, and ADX reduce lymphocyte cell death (6,15,43). Furthermore, surgical removal of the adrenal glands is associated with less DNA fragmentation and lower nitric oxide production of splenic macrophages (5).…”

Section: Discussionmentioning

confidence: 99%

Adrenalectomy in mice does not prevent loss of intestinal lymphocytes after exercise

Hoffman‐Goetz

Quadrilatero

Boudreau

et al. 2004

Journal of Applied Physiology

View full text Add to dashboard Cite

Exhaustive exercise is associated with an increase in circulating glucocorticoids (GCs), lymphocyte apoptosis, and a reduction in intestinal lymphocyte number. The present study examined the role of GCs on the numerical changes seen in intestinal lymphocytes after exercise. Female C57BL/6 mice were bilaterally adrenalectomized (ADX; n ϭ 18) or given sham surgery (Sham; n ϭ 18) and assigned to one of three exercise conditions: treadmill running (28 m/min, 90 min, 2°slope) and killed immediately or after 24 h recovery, or not exercised and killed immediately after 90-min exposure to the treadmill environment. Lymphocytes were isolated from the intestines with CD45 ϩ cells collected by positive selection using magnetic bead separation columns, and lymphocyte subpopulations were analyzed by flow cytometry for CD45 ϩ , CD3␣␤ ϩ , CD3␥␦ ϩ , CD8␤ ϩ , CD8␣ ϩ , CD4 ϩ , and NK ϩ phenotypic markers. ADX mice had significantly more intestinal CD45 ϩ leukocytes (P Ͻ 0.05) and CD3␣␤ ϩ (P Ͻ 0.05), CD3␥␦ ϩ (P Ͻ 0.01), CD8␣ ϩ (P Ͻ 0.001), and NK ϩ (P Ͻ 0.05) intestinal lymphocytes than Sham mice. There was a significant effect of exercise condition on total intestinal CD45 ϩ leukocytes (P Ͻ 0.01) and CD3␣␤ ϩ (P Ͻ 0.05), CD8␣ ϩ (P Ͻ 0.001), and CD4 ϩ (P Ͻ 0.05) intestinal lymphocytes, with fewer cells at 24 h postexercise compared with the other treatment conditions. There were no surgical ϫ exercise interaction effects on the CD3 and CD8 phenotype numbers. Plasma corticosterone was virtually nil in ADX mice regardless of exercise condition but was significantly elevated in Sham mice immediately postexercise (P Ͻ 0.001). The data indicate that ADX does not prevent the loss of lymphocytes from the intestinal mucosa 24 h after strenuous exercise and GCs are not directly causal in the leukopenia of exercise. treadmill running; adrenal glands; glucocorticoids NUMEROUS STUDIES HAVE SHOWN that acute exercise is associated with induction of apoptosis or programmed cell death and loss of lymphocytes from blood, thymus, and spleen in humans and laboratory animals (9,20,28,29). Lymphocyte loss and/or apoptosis have been observed in other situations characterized by extreme physiological stress, including burn injury (15), electrical shock (48), and chronic restraint stress (42), and may reflect release of stress hormones, in particular glucocorticoids (GCs). GCs trigger apoptosis in lymphocytes by acting on an intracellular pathway via the mitochondria (2), which results in the accumulation of mitochondrial derived cytochrome c within the cytosol, loss of mitochondrial membrane integrity, externalization of phosphatidylserine at cell membranes, and DNA fragmentation (27,45).The intestinal intraepithelial lymphocytes (IELs) are a unique population of T cells that function as a first line of defense against exogenous pathogens, many of which develop independently of the thymus gland [i.e., T cells with the ␥␦ form of the T cell receptor (TCR)] (35). IELs play an important role in protection from epithelial tumor cells through their function a...

show abstract

Section: Discussionmentioning

confidence: 99%

Adrenalectomy in mice does not prevent loss of intestinal lymphocytes after exercise

Hoffman‐Goetz

Quadrilatero

Boudreau

et al. 2004

Journal of Applied Physiology

View full text Add to dashboard Cite

show abstract

“…Tissue samples from duodenum and mid-jejunum were pooled for IEL isolation. The IEL were isolated by previously published protocols, which were adapted to canine lymphocytes [2,15]. In brief, IEL were dissociated from intestinal tissue by gently stirring tissue pieces in Ca 2+ -and Mg 2+ -free HBSS containing 2% horse serum, 1 mM DTT, and 0.5 mM EDTA for 2 · 30 min at 37°C.…”

Section: Iel Isolationmentioning

confidence: 99%

Phenotyping, functional characterization, and developmental changes in canine intestinal intraepithelial lymphocytes

et al. 2009

View full text Add to dashboard Cite

-Little is currently known about the lymphocyte populations in the normal and diseased canine gut. The aim of this study was thus the phenotypical and functional characterization of canine intestinal intraepithelial lymphocytes (IEL). IEL were isolated from full-thickness biopsies of 15 adult Swiss Beagle dogs (mean age 8.2 ± 2.8 years) and compared to mesenteric lymph node cells. The phenotypical characterization by multi-parameter flow cytometry revealed that canine IEL differ substantially from lymph node T cells, and consist of various unconventional lymphocyte subsets, unique to mucosal surfaces. These include cd T cells, and CD4 À CD8 À and CD8aa + T cells. IEL populations in adult dogs were also compared to those isolated from neonatal Beagle dogs. Analysis revealed a high frequency of undifferentiated CD4 À CD8 À T cells in newborn dogs whereas mature CD4 + and CD8 + T cells predominate in adult dogs, indicating maturation of the intestinal immune system during development. As IEL in other species are thought to exhibit regulatory functions, we investigated the role of IEL on the activation-induced proliferation of lymph node T cells. While IEL alone did not show activation-induced proliferation, they significantly inhibited the proliferation of activated lymph node T cells in a cell number-dependent manner. These findings are the first to demonstrate that canine intestinal IEL have an immunoregulatory phenotype, which may contribute to the maintenance of intestinal immune homeostasis and may, therefore, be lost in canine chronic enteropathies.dog / intestine / intraepithelial lymphocyte

show abstract

“…In some experiments, splenocytes were pre-incubated with the GC receptor antagonist 100 nM RU486 (Brunner et al, 2001). After 2 h, cells were stimulated with 1 mg/ml concanavalin A for 20 h, and CD69 expression on CD4 þ T cells (antibodies from eBiosciences, San Diego, CA, USA) was detected by flow cytometry.…”

Section: T-cell Activation Assaymentioning

confidence: 99%

Colon cancer cells produce immunoregulatory glucocorticoids

et al. 2011

Self Cite

View full text Add to dashboard Cite

Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape.

show abstract

Regulation of cell death and survival in intestinal intraepithelial lymphocytes

Cited by 47 publications

References 65 publications

Adrenalectomy in mice does not prevent loss of intestinal lymphocytes after exercise

Adrenalectomy in mice does not prevent loss of intestinal lymphocytes after exercise

Phenotyping, functional characterization, and developmental changes in canine intestinal intraepithelial lymphocytes

Colon cancer cells produce immunoregulatory glucocorticoids

Contact Info

Product

Resources

About