Trends in Immunology
ReviewT-cell recruitment to the intestinal mucosa
Section snippets
T-lymphocyte populations in the intestinal mucosa
The intestinal mucosa contains a large number of T cells, localized within gut-associated lymphoid tissue (GALT), including Peyer’s patches (PP) and solitary isolated lymphoid structures, or diffusely throughout the intestinal lamina propria (LP) and overlying single layered epithelium. LP lymphocytes (LPLs) are primarily conventional CD4+TCRαβ+ or CD8αβ+TCRαβ+ T cells that display a previously activated or memory phenotype and enter the intestinal mucosa subsequent to their priming and
Effector T cells
T-cell entry into lymphoid and extralymphoid tissues is regulated by the coordinated interaction of cellular adhesion receptors on T cells and their respective ligands on vascular endothelial cells. The selective expression of cellular adhesion receptors on T cells and vascular endothelium is of fundamental importance in guiding T-cell subsets into and through distinct tissue compartments. Several cellular adhesion receptors have been implicated in regulating T-cell entry to and/or localization
CCR9-independent T-cell localization to the small intestinal mucosa
Although CCR9−/− and CCL25−/− mice have reduced numbers of small intestinal IELs, this reduction, as described above, is primarily within the CD8ααTCRγδ IEL compartment 38, 39, 40. CCR9−/− and CCL25−/− mice also have normal numbers of CD4+ LPLs and only a slight reduction in CD8+ LPLs [40]. Thus, CCR9 and CCL25 are not absolutely required for the localization and/or maintenance of conventional T cells within the intestinal mucosa. The abundance of intestinal T cells in CCR9−/− and CCL25−/− mice
Generation of CCR9+α4β7+ ‘gut tropic’ effector T cells in vivo
Our understanding of the mechanisms regulating the generation of tissue tropic, and in particular ‘gut homing’ T-cell subsets, has increased dramatically in the last few years. In TCR transgenic adoptive transfer models, injection of model antigen (ovalbumin) and adjuvant intraperitoneally induced the expression of CCR9 and α4β7 on responding CD4+ and CD8+ T cells selectively in mesenteric but not peripheral LNs or the spleen 17, 49, indicating a specific role for the local environment in the
CD103+ dendritic cells and the generation of ‘gut tropic’ T cells
It is well recognized that dendritic cells (DCs) play a central role in the priming and differentiation of naïve T cells. Recent studies have also demonstrated that MLN and PP DCs have an enhanced ability to induce gut homing receptors on responding T cells in vitro and thus potentially contribute to the selective generation of gut tropic T cells in these SLOs 16, 57, 58. When PP DCs were sorted into distinct subsets based on their expression of the conventional DC markers CD8, B220 and CD11b,
Retinoic acid receptor signaling and the generation of ‘gut tropic’ T cells
Although the molecular mechanisms regulating gut homing receptor expression on PP- and MLN-primed T cells remain to be fully elucidated, a key inducer of gut homing receptors seems to be the vitamin A (retinol) metabolite, retinoic acid (RA) [66]. Intracellular synthesis of RA occurs through the sequential oxidation of vitamin A to retinal and retinal’s subsequent oxidation to RA, the latter process being dependent on retinal dehydrogenases (RALDHs) [67]. RA is a major physiologically active
Role of CD103+ MLN DCs in the generation of gut tropic T cells in vivo
While CD103+ MLN DCs efficiently generate gut tropic T-cell populations in vitro, their importance in regulating T-cell tropism in vivo is currently unclear. Several studies have demonstrated that intraperitoneal injection of antigen-loaded nonintestinal DCs induces α4β7 expression on responding T cells in the MLNs 68, 77, indicating that adoptively transferred nonintestinal DCs can be imprinted with the ability to generate gut tropic T cells in the MLN. However, because CD103− MLN DCs do not
Imprinting of CD103+ small intestinal LP DCs
CD103+ MLN DCs express CCR7 and higher levels of co-stimulatory molecules than their CD103− counterparts, and their numbers are markedly reduced in CCR7−/− mice, indicating that they represent a tissue-derived migratory population 50, 78, 79. Indeed, results from BrdU (bromodeoxyuridine) pulse-chase experiments suggest that the majority of CD103+ MLN DCs are CD103+ DCs that have migrated from the small intestinal LP [65], whereas most CD103− MLN DCs seem to represent an LN resident population,
T-cell recruitment to the colonic mucosa
Compared with the small intestine, the mechanisms regulating T-cell recruitment to the colonic LP and epithelium remain poorly defined. The composition of the colonic IEL compartment differs significantly from that of the small intestine; for example, the majority of murine colonic IELs are TCRαβ+, and most of these cells are CD4+4, 5. Furthermore, many colonic IELs express L-selectin 4, 5 and are CD69−CD44lo and thus display the phenotype of naïve T cells 83, 84. L-selectinhi colonic IELs, in
Concluding remarks
Recent years have seen a significant progress in our understanding of the mechanisms regulating the generation and localization of T cells to the intestinal mucosa. Key findings include the realization that small intestinal tropic T cells are selectively generated in MLNs and PPs, the demonstration that the vitamin A metabolite, RA, selectively induces gut homing receptor expression and the finding that CD103+ small intestinal LP and MLN DCs display an enhanced ability to induce RAR signaling
Acknowledgements
I thank B. Johansson-Lindbom (Lund University) for reading and critique of the manuscript. This work was supported by grants from the Swedish Medical Research Council, the Österlund Foundation, the Royal Physiographic Society, the Wellcome Trust and the Swedish Foundation for Strategic Research INGVAR II program.
References (90)
- et al.
Brokering the peace: the origin of intestinal T cells
Mucosal Immunol.
(2008) Crohn’s disease: beyond antagonists of tumour necrosis factor
Lancet
(2008)Identification of pre- and postselection TCRalphabeta+ intraepithelial lymphocyte precursors in the thymus
Immunity
(2006)Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes
Blood
(2001)Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells
Mucosal Immunol.
(2008)Gut-associated lymphoid tissue-primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine
Blood
(2006)Retinoic acid imprints gut-homing specificity on T cells
Immunity
(2004)The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
Cell
(2006)Role of beta7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn’s disease
Gastroenterology
(2008)Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis
Gastroenterology
(2006)
Human CD8+ intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue
Immunol. Rev.
Thymic differentiation of TCR alpha beta(+) CD8 alpha alpha(+) IELs
Immunol. Rev.
Regional specialization of the mucosal immune system. Intraepithelial lymphocytes of the large intestine have a different phenotype and function than those of the small intestine
J. Immunol.
Regional specialization of intraepithelial T cells in the murine small and large intestine
Scand. J. Immunol.
Regional variation in the proliferative rate and lifespan of alpha beta TCR+ and gamma delta TCR+ intraepithelial lymphocytes in the murine small intestine
Immunology
IELs: enforcing law and order in the court of the intestinal epithelium
Immunol. Rev.
Intraepithelial lymphocytes: their shared and divergent immunological behaviors in the small and large intestine
Immunol. Rev.
Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue
Am. J. Pathol.
Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin
Nature
The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9
Eur. J. Immunol.
Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity
J. Exp. Med.
The role of beta7 integrins in CD8 T cell trafficking during an antiviral immune response
J. Exp. Med.
Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo
J. Immunol.
Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant
J. Exp. Med.
CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa
J. Clin. Invest.
Differential homing mechanisms regulate regionalized effector CD8alphabeta+ T cell accumulation within the small intestine
Proc. Natl. Acad. Sci. U. S. A.
Commensal bacteria and expression of two major intestinal chemokines, TECK/CCL25 and MEC/CCL28, and their receptors
PLoS One
Functional characterization of the CCL25 promoter in small intestinal epithelial cells suggests a regulatory role for caudal-related homeobox (Cdx) transcription factors
J. Immunol.
CC chemokine ligands 25 and 28 play essential roles in intestinal extravasation of IgA antibody-secreting cells
J. Immunol.
The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system
J. Immunol.
Demonstration of functional role of TECK/CCL25 in T lymphocyte-endothelium interaction in inflamed and uninflamed intestinal mucosa
Am. J. Physiol. Gastrointest. Liver Physiol.
CCL25 and CCL28 promote alpha4beta7 integrin dependent adhesion of lymphocytes to MadCAM-1 under shear-flow
Am. J. Physiol. Gastrointest. Liver Physiol.
A critical role for CD40-CD40 ligand interactions in amplification of the mucosal CD8 T cell response
J. Exp. Med.
CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes
Eur. J. Immunol.
TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease
J. Exp. Med.
Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice
J. Immunol.
CD8+ recent thymic emigrants home to and efficiently repopulate the small intestine epithelium
Nat. Immunol.
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
J. Exp. Med.
Age-related changes in CCR9+ circulating lymphocytes: are CCR9+ naive T cells recent thymic emigrants?
Scand. J. Immunol.
Curriculum vitae of intestinal intraepithelial T cells: their developmental and behavioral characteristics
Immunol. Rev.
The extrathymic T-cell differentiation in the murine gut
Immunol. Rev.
Enterocyte expression of interleukin 7 induces development of gammadelta T cells and Peyer’s patches
J. Exp. Med.
Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue
Nature
Involvement of CCL25 (TECK) in the generation of the murine small-intestinal CD8alpha alpha+CD3+ intraepithelial lymphocyte compartment
Eur. J. Immunol.
A role for CCR9 in T lymphocyte development and migration
J. Immunol.
Cited by (131)
Polyphenol and glucosinolate-derived AhR modulators regulate GPR15 expression on human CD4+ T cells
2023, Journal of Nutritional BiochemistryEnforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity
2023, American Journal of TransplantationPlatycodon grandiflorus polysaccharide regulates colonic immunity through mesenteric lymphatic circulation to attenuate ulcerative colitis
2023, Chinese Journal of Natural MedicinesImpact of gut microenvironment on epigenetic signatures of intestinal T helper cell subsets
2022, Immunology LettersIsolation and immunophenotyping by flow cytometry of canine peripheral blood and intraepithelial and lamina propria duodenal T lymphocytes
2021, Veterinary Immunology and ImmunopathologyIntraepithelial Lymphocytes Suppress Intestinal Tumor Growth by Cell-to-Cell Contact via CD103/E-Cadherin Signal
2021, Cellular and Molecular Gastroenterology and Hepatology