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  • Review Article
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Acquired and natural memory T cells join forces at the mucosal front line

Nature Reviews Immunology volume 4, pages 290–300 (2004)Cite this article

Key Points

  • Together with the passive protection of an impermeable barrier, an active adaptive immune system has evolved in the intestine of higher vertebrates.

  • The intestine consists of two immunological compartments: the initiation compartment, containing the organized lymphoid structures of the gut-associated lymphoid tissue (GALT), and the effector compartment, consisting of the diffuse immune cells of the lamina propria and intestinal epithelium.

  • The adaptive immune system, which allows for the formation of immune memory, is prominent at the mucosal site. In mammals, the intestine is an important T-cell organ and two distinct subsets of memory T cells have evolved at mucosal surfaces.

  • The natural and acquired memory T-cell subsets differ from each other in the nature of the antigens they recognize and the differentiation pathway they take to achieve a memory phenotype.

  • Natural memory T cells are self-specific and gained gut tropism and a memory phenotype during agonist selection in the thymus. These natural memory mucosal T cells respond to self-antigens of stressed epithelial cells and regulate immune responses of the conventional mucosal T cells. The γδ-TCR+ subset also has tissue-repair ability.

  • Acquired memory T cells are non-self-specific and gained gut tropism and mucosal memory differentiation through specific recognition of antigen presented by mucosal dendritic cells. The acquired memory mucosal T cells respond to foreign antigens derived from invading pathogens. They clear the pathogen in a highly regulated manner.

  • The joint efforts of these two subsets of memory T cells allow for the most effective protection, while preserving integrity of the barrier at the mucosal front line in higher vertebrates.

Abstract

The intestine is fundamental for the uptake of fluids and nutrients, but it also provides a main entrance for pathogens. This unique challenge has imposed an important evolutionary drive for distinctive specialization of the mucosal defence mechanisms. A hallmark of the modern immune system is its ability to generate antigen-specific memory T cells, which can provide immediate, potent and long-lasting protection. The high demand for effective protection, which is also compatable with vital functions of the intestine, has ensured that unique subsets of memory T cells have evolved at the mucosal front line. This review discusses the various mucosal T-cell subsets, and the new insights we have gained in understanding their specific differentiation and unique functions.

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Figure 1: Immune effector and initiation sites at the gut epithelium.
Figure 2: Mechanisms of antigen uptake in the gut.
Figure 3: Sentinels at the gut epithelium.
Figure 4: A schematic representation of different selection outcomes in the thymus, based on signal strength of the TCR interaction with self-antigens.

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Acknowledgements

We thank M. Cheroutre for her important contribution and M. Kronenberg for helpful discussions and his continuous support.

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Authors and Affiliations

  1. Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, 92121, California, USA

    Hilde Cheroutre & Loui Madakamutil

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  1. Hilde Cheroutre
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Correspondence to Hilde Cheroutre.

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DATABASES

LocusLink

CCL25

CCL28

CCR9

CCR11

CD2

CD16

CD28

CD62L

CD80

CD86

CX3CL1

CXCL12

FcεRIγ

MADCAM1

TGF-β

Thy1

Glossary

TIGHT JUNCTIONS

Dynamic structures that consist of proteins, including occludin, claudin 1 and junctional adhesion molecule, that seal neighbouring cells together to prevent paracellular traffic of macromolecules and microorganisms.

ENTEROCYTES

Absorbing epithelial cells that form a single-cell layer that lines the luminal side of the intestine.

PEYER'S PATCHES

Organized lymphoid compartments that are integrated into the walls of the small intestine.

LAMINA PROPRIA

A meshwork of connective tissue that underlies the gut epithelium, containing a broad spectrum of myeloid and lymphoid cells.

OLIGOCLONAL

A T-cell receptor (TCR) repertoire with a limited number of TCR clones.

AGONIST PEPTIDES

Cognate antigenic peptides that can stimulate the T-cell receptor in a productive manner.

M CELLS

Specialized epithelial cells that deliver antigens by trans-epithelial vesicular transport from the gut lumen directly to the sub-epithelial lymphoid tissues of the Peyer's patch.

MHC TETRAMERS

Reagents composed of four peptide–MHC complexes linked by biotinylation, which can be fluorescently labelled and used to detect antigen-specific T cells by flow cytometry.

COLITIS

An inflammatory bowel disease characterized by contiguous inflammation of the gut mucosa, mainly of the large intestine.

ANTAGONIST PEPTIDE

Cognate peptide that stimulates the T-cell receptor in a non-productive manner.

NUDE

A mutation in mice that causes both hairlessness and defective thymus formation, which results in the absence of mature T cells.

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Cheroutre, H., Madakamutil, L. Acquired and natural memory T cells join forces at the mucosal front line. Nat Rev Immunol 4, 290–300 (2004). https://doi.org/10.1038/nri1333

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