Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment

The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4+ and CD8+ T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9+, and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9−. TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

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Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis

Journal of Experimental Medicine ◽

10.1084/jem.190.9.1241 ◽

1999 ◽

Vol 190 (9) ◽

pp. 1241-1256 ◽

Cited By ~ 352

Author(s):

Brian A. Zabel ◽

William W. Agace ◽

James J. Campbell ◽

Heidi M. Heath ◽

David Parent ◽

...

Keyword(s):

Small Intestine ◽

T Lymphocytes ◽

G Protein ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Intraepithelial Lymphocytes ◽

Mucosal Immune Response ◽

G Protein Coupled Receptor ◽

Cc Chemokine ◽

G Protein Coupled

TECK (thymus-expressed chemokine), a recently described CC chemokine expressed in thymus and small intestine, was found to mediate chemotaxis of human G protein–coupled receptor GPR-9-6/L1.2 transfectants. This activity was blocked by anti–GPR-9-6 monoclonal antibody (mAb) 3C3. GPR-9-6 is expressed on a subset of memory α4β7high intestinal trafficking CD4 and CD8 lymphocytes. In addition, all intestinal lamina propria and intraepithelial lymphocytes express GPR-9-6. In contrast, GPR-9-6 is not displayed on cutaneous lymphocyte antigen–positive (CLA+) memory CD4 and CD8 lymphocytes, which traffic to skin inflammatory sites, or on other systemic α4β7−CLA− memory CD4/CD8 lymphocytes. The majority of thymocytes also express GPR-9-6, but natural killer cells, monocytes, eosinophils, basophils, and neutrophils are GPR-9-6 negative. Transcripts of GPR-9-6 and TECK are present in both small intestine and thymus. Importantly, the expression profile of GPR-9-6 correlates with migration to TECK of blood T lymphocytes and thymocytes. As migration of these cells is blocked by anti–GPR-9-6 mAb 3C3, we conclude that GPR-9-6 is the principal chemokine receptor for TECK. In agreement with the nomenclature rules for chemokine receptors, we propose the designation CCR-9 for GPR-9-6. The selective expression of TECK and GPR-9-6 in thymus and small intestine implies a dual role for GPR-9-6/CCR-9, both in T cell development and the mucosal immune response.

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The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes

Cell Death and Differentiation ◽

10.1038/s41418-021-00921-w ◽

2022 ◽

Author(s):

Haohao Zhang ◽

Yiming Hu ◽

Dandan Liu ◽

Zhi Liu ◽

Ningxia Xie ◽

...

Keyword(s):

Molecular Mechanisms ◽

Immune Surveillance ◽

Intraepithelial Lymphocytes ◽

Target Cells ◽

Histone 3 ◽

Intestinal Intraepithelial Lymphocytes ◽

H3k27me3 Level ◽

Small Intestinal ◽

And Function ◽

Cytotoxic Function

AbstractIntestinal intraepithelial lymphocytes (IELs) are distributed along the length of the intestine and are considered the frontline of immune surveillance. The precise molecular mechanisms, especially epigenetic regulation, of their development and function are poorly understood. The trimethylation of histone 3 at lysine 27 (H3K27Me3) is a kind of histone modifications and associated with gene repression. Kdm6b is an epigenetic enzyme responsible for the demethylation of H3K27Me3 and thus promotes gene expression. Here we identified Kdm6b as an important intracellular regulator of small intestinal IELs. Mice genetically deficient for Kdm6b showed greatly reduced numbers of TCRαβ+CD8αα+ IELs. In the absence of Kdm6b, TCRαβ+CD8αα+ IELs exhibited increased apoptosis, disturbed maturation and a compromised capability to lyse target cells. Both IL-15 and Kdm6b-mediated demethylation of histone 3 at lysine 27 are responsible for the maturation of TCRαβ+CD8αα+ IELs through upregulating the expression of Gzmb and Fasl. In addition, Kdm6b also regulates the expression of the gut-homing molecule CCR9 by controlling H3K27Me3 level at its promoter. However, Kdm6b is dispensable for the reactivity of thymic precursors of TCRαβ+CD8αα+ IELs (IELPs) to IL-15 and TGF-β. In conclusion, we showed that Kdm6b plays critical roles in the maturation and cytotoxic function of small intestinal TCRαβ+CD8αα+ IELs.

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Molecular regulation of CC-chemokine receptor 3 expression in human T helper 2 cells

Blood ◽

10.1182/blood.v98.8.2568 ◽

2001 ◽

Vol 98 (8) ◽

pp. 2568-2570 ◽

Cited By ~ 17

Author(s):

Emmanuel Scotet ◽

Susanne Schroeder ◽

Antonio Lanzavecchia

Keyword(s):

T Cells ◽

Chromatin Remodeling ◽

Chemokine Receptor ◽

Molecular Mechanisms ◽

Regulatory Element ◽

Th2 Cells ◽

Specific Gene ◽

Upstream Sequence ◽

T Helper ◽

Cc Chemokine

Abstract In developing T helper 1 (Th1) and Th2 cells the acquisition of effector function is intimately connected with the acquisition of new migratory capacities, as exemplified by differential expression of chemokine receptors. This study investigates the molecular mechanisms responsible for Th2-restricted expression of the CC-chemokine receptor 3 (CCR3). The minimal promoter in T cells was identified in the −149 base pair (bp) upstream sequence that contains a positive regulatory element. A strong negative element was also localized in the flanking intronic sequence. The study further investigates the role of chromatin remodeling in the regulation of this Th2-specific gene. Drugs that affect the chromatin structure facilitate CCR3 expression in T cells. Furthermore, in differentiating Th2 cells, selected regions are associated with acetylated-H3 histones and become more accessible to DNase I. These results suggest that in Th2 cells both cytokine production and migratory capacity are regulated through a similar mechanism involving chromatin remodeling.

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Upregulation of ICOS on CD43+ CD4+ murine small intestinal intraepithelial lymphocytes during acute reovirus infection

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.02.031 ◽

2006 ◽

Vol 342 (3) ◽

pp. 782-790 ◽

Cited By ~ 8

Author(s):

Dina Montufar-Solis ◽

Tomas Garza ◽

Ba-Bie Teng ◽

John R. Klein

Keyword(s):

Intraepithelial Lymphocytes ◽

Reovirus Infection ◽

Intestinal Intraepithelial Lymphocytes ◽

Small Intestinal

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Nutritional and Physiological Constraints Contributing to Limitations in Small Intestinal Starch Digestion and Glucose Absorption in Ruminants

Ruminants ◽

10.3390/ruminants2010001 ◽

2021 ◽

Vol 2 (1) ◽

pp. 1-26

Author(s):

Ronald J. Trotta ◽

David L. Harmon ◽

James C. Matthews ◽

Kendall C. Swanson

Keyword(s):

Small Intestine ◽

Molecular Mechanisms ◽

Glucose Absorption ◽

Feeding Strategies ◽

Starch Digestion ◽

Sucrase Activity ◽

Physiological Constraints ◽

Small Intestinal ◽

Intestinal Sucrase ◽

Intestinal Sucrase Activity

Increased efficiency of nutrient utilization can potentially be gained with increased starch digestion in the small intestine in ruminants. However, ruminants have quantitative limits in the extent of starch disappearance in the small intestine. The objective is to explore the nutritional and physiological constraints that contribute to limitations of carbohydrate assimilation in the ruminant small intestine. Altered digesta composition and passage rate in the small intestine, insufficient pancreatic α-amylase and/or small intestinal carbohydrase activity, and reduced glucose absorption could all be potentially limiting factors of intestinal starch assimilation. The absence of intestinal sucrase activity in ruminants may be related to quantitative limits in small intestinal starch hydrolysis. Multiple sequence alignment of the sucrase-isomaltase complex gives insight into potential molecular mechanisms that may be associated with the absence of intestinal sucrase activity, reduced capacity for intestinal starch digestion, and limitations in the efficiency of feed utilization in cattle and sheep. Future research efforts in these areas will aid in our understanding of small intestinal starch digestion and glucose absorption to optimize feeding strategies for increased meat and milk production efficiency.

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