Attributes of γδ intraepithelial lymphocytes as suggested by their transcriptional profile

Abstract

␥␦ T lymphocytes in the intestinal intraepithelial layer (␥␦ IELs) are thought to contribute to immune competence, but their actual function remains poorly understood. Here we used DNA microarrays to study the gene expression profile of ␥␦ IELs in a Yersinia infection system to better define their roles. To validate this approach, mesenteric lymph node CD8 ؉ ␣␤ T cells were similarly analyzed. The transcription profiles show that, whereas lymph node CD8 ؉ ␣␤ T cells must be activated to become cytotoxic effectors, ␥␦ IELs are constitutively activated and appear to use different signaling cascades. Our data suggest that ␥␦ IELs may respond efficiently to a broad range of pathological situations irrespective of their diverse T cell antigen receptor repertoire. ␥␦ IELs may modulate local immune responses and participate in intestinal lipid metabolism, cholesterol homeostasis, and physiology. This study provides a strong basis for further investigations of the roles of these cells as well as mucosal immune defense in general.D espite intense efforts, the functional roles of ␥␦ T cells in maintaining host immune defense remain enigmatic. One unique feature of ␥␦ T cells that distinguishes them from ␣␤ T cells is their tissue distribution. Although ␥␦ T cells represent a small percentage (Ͻ5%) of the lymphocytes in the central immune system of humans and mice, they are a sizable population (10 -50%) in the mucosal epithelia (1, 2). The murine ␥␦ T lymphocytes in the intestinal intraepithelial layer (␥␦ IELs) exhibit a diverse T cell antigen receptor (TCR) repertoire (3, 4) and thus have the potential to recognize a variety of antigens. These cells have been implicated in regulating the development of epithelial cells (5) and in controlling intestinal ␣␤ T cell responses in an Eimeria vermiformis infection model (6). Recently, we found that mice lacking ␥␦ T cells (TCR␦ Ϫ/Ϫ ) are much less resistant than either normal mice or mice without ␣␤ T cells (TCR␤ Ϫ/Ϫ ) to the dissemination of the enteric pathogen Yersinia pseudotuberculosis to the liver and spleen 1-4 days after oral infection (7). To gain insight into the scope of ␥␦ IEL responses in this system, we compared the gene expression of ␥␦ IELs isolated from mice orally infected with Yersinia to that of ␥␦ IELs isolated from uninfected animals by using the Affymetrix (Santa Clara, CA) GENECHIP technology (8). This approach allowed us to examine a large number of transcripts including many not associated with lymphocyte functions and to gain insight into the cellular mechanisms operating in ␥␦ IELs. To validate the experimental approach, and to serve as a basis of comparison for the ␥␦ IEL data, we also analyzed the expression profiles of mesenteric lymph node (MLN) CD8 ϩ ␣␤ T cells at the peak of the peripheral responses to oral Yersinia infection (7).We find that, whereas transcripts associated with cytotoxic functions and activation are significantly induced in CD8 ϩ ␣␤ T cells by the infection, ␥␦ IELs from infected and uninfected animals appear to be constituti...

Surface expression of HSP72 by LPS‐stimulated neutrophils facilitates γδT cell‐mediated killing

“…Our data suggest that HSP72 could serve as an important regulatory signal that exposes PMN to immunological attack by cdT cells. This notion is supported by reports that surface expression of HSP72 serves as a targeting molecule for NK cells [30,31] and that human, murine and rat cdT cells express NK-associated genes and possess NK-like cytolytic activity [15,32,33].…”

Cutting Edge: A Chemical Genetic System for the Analysis of Kinases Regulating T Cell Development

“…Indeed, whereas identification of cell lines or transgenic mice expressing a biologically relevant level of a transgene can be problematic, the capacity to use ASKAs to regulate kinase activity may allow one to use mice or cell lines grossly overexpressing a particular kinase. The relative ease of ASKA construction (successfully applied to v-Src, CDK2, Fus3, CAMKII␣ (4)), the specificity of the inhibitor's effects; the broad range of kinase activity achievable, and the closer correlation of biological outcome with kinase activity, as opposed to inducible levels of gene expression (26,27) suggest that ASKA technology should be usefully applied to many kinases emerging from the expression profiling of lymphoid cells (28,29) and from genome sequencing.…”

Role for E-Cadherin as an Inhibitory Receptor on Epidermal γδ T Cells

“…In addition to the inhibitory role for E-cadherin in epithelial cells, ligation of E-cadherin on Langerhans cells has been shown to inhibit their maturation and chemokine production (45,46). Besides DETCs, murine intestinal IELs (47,48) and a subset of mast cells (49) express E-cadherin, as well as a E b 7 integrin. Although in humans, E-cadherin expression has not been detected on intestinal IELs (26) or other lymphocytes, some human T cell neoplasms express N-cadherin (50)(51)(52)(53)(54).…”