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  • Review Article
  • Published:

Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation

Nature Reviews Immunology volume 4, pages 325–336 (2004)Cite this article

Key Points

  • Activated T cells acquire the ability to home to extralymphoid sites, including the lungs, skin, gastrointestinal tract and central nervous system, where they can enter extravascular tissues even in the absence of inflammation. They can also enter almost any site of inflammation.

  • Activated effector and central memory T cells use selectins and selectin ligands to enter some of these sites: most prominently E-selectin for the skin, L-selectin for the inflamed pancreas and salivary glands, and P-selectin for the lamina-propria compartment of the gastrointestinal tract.

  • All T cells express P-selectin glycoprotein ligand 1 (PSGL1), but PSGL1 is not functional in naive T cells, in which the necessary glycosyltransferases are not expressed. Regulated glycosyltransferases in T cells include fucosyltransferase-VII (FucT-VII), core 2 β1,6-glucosaminyltransferase-I (C2GlcNAcT-I) and sialyl 3-galactosyltransferase-IV (ST3Gal-IV).

  • T helper 1 (TH1) cells express more FucT-VII, C2GlcNAcT-I and ST3Gal than TH2 cells and bind E-selectin much better, but some TH2 cells can also bind E-selectin. FucT-VII is the limiting enzyme for E-selectin-binding activity, which is detected by binding of monoclonal antibody HECA-452, whereas C2GlcNAcT-I determines P- and L-selectin-ligand activity in T cells.

  • FucT-VII and C2GlcNAcT-I are independently regulated. Whereas FucT-VII is expressed after T-cell receptor ligation through a RAS-dependent pathway with additional signals from the interleukin-12 receptor (IL-12R) through unknown signalling molecules, C2GlcNAcT-I is under the control of the IL-12R through signal transducer and activator of transcription 4 (STAT4).

  • Naive T cells express L-selectin, but cannot enter most extralymphoid sites. Some T cells, including central memory cells, re-express L-selectin after antigen encounter and can home to sites of chronic inflammation, where the L-selectin ligand peripheral node addressin (PNAD), detected by monoclonal antibody MECA-79, is expressed through the induction of high endothelial cell (HEC)-GlcNAc6ST expression, especially in inflamed exocrine and endocrine glands.

  • Endothelial cells express P- and E-selectin constitutively in the skin and inducibly in many organs during acute and chronic inflammation. At sites of inflammation, T-cell interactions are likely to involve selectin-dependent interactions with myeloid leukocytes, platelets, and leukocyte- and platelet-derived microparticles, which complicate the interpretation of experiments using knockout mice or antibody blockade of selectins or their ligands.

Abstract

The ability to home to extralymphoid tissues, such as the skin, lungs and gut, is acquired by many effector and memory T cells after initial antigen encounter. This review discusses the role of E-, P- and L-selectin and their glycoprotein ligands in this process. During activation, some T cells differentiate to bind E-selectin through induced expression of fucosyltransferase-VII and to bind P- and L-selectin through additional expression of core 2 glucosaminyltransferase-I. This inducible expression of selectin ligands, together with the regulation of L-selectin expression, has a role in the recruitment of activated T cells to extralymphoid tissues and sites of inflammation.

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Figure 1: T-cell trafficking patterns.
Figure 2: Prototypic selectin ligand.
Figure 3: Selectin and selectin-ligand expression by CD4+ T cells.
Figure 4: Regulation of glycosyltransferases that determine selectin-ligand activity.
Figure 5: Selectin-dependent T-cell interactions in extralymphoid blood vessels.

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Acknowledgements

This work was supported by the National Institutes of Health.

Author information

Authors and Affiliations

  1. Cardiovascular Research Center and Departments of Biomedical Engineering, Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, 22908, Virginia, USA

    Klaus Ley

  2. Department of Microbiology and Immunology, The Feinberg Medical School of Northwestern University, Chicago, 60611, Illinois, USA

    Geoffrey S. Kansas

Authors
  1. Klaus Ley
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Correspondence to Klaus Ley.

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Related links

Related links

DATABASES

LocusLink

CCR7

CD34

E-selectin

L-selectin

P-selectin

PSGL1

STAT4

STAT5

STAT6

T-bet

FURTHER INFORMATION

The Leukocyte Adhesion Cascade

Klaus Ley's laboratory webpage

Glossary

TETHERING OR CAPTURE

The initial, transient adhesive contact of a T cell with the endothelium or an adherent leukocyte or platelet.

C-TYPE LECTINS

Calcium-dependent animal lectins that are carbohydrate-binding proteins. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain (CRD), which is highly conserved among this family. Calcium is essential not only for the carbohydrate binding itself, but it also contributes to the structural maintenance of this domain.

LEUKOCYTE ROLLING ASSAYS

Assays in which T cells or other leukocytes are allowed to interact with endothelial cells or recombinant adhesion molecules in the presence of shear stress, usually induced by perfusing blood or cell-culture media. These assays are essential for testing physiologically relevant selectin-mediated interactions.

SIALYL-LEWIS X

(sLex). Sialylated and fucosylated tetrasaccharide (GlcNAc(α1,3Fuc)β1,4Galα2,3Sia) related to selectin ligands.

HIGH ENDOTHELIAL VENULES

(HEVs). The site of entry for lymphocytes from the blood stream into lymph nodes and Peyer's patches.

CENTRAL MEMORY T CELLS

Memory T cells that express L-selectin and CC-chemokine receptor 7, and can be found in the blood and lymphoid organs.

EFFECTOR MEMORY T CELLS

Memory T cells that do not express either L-selectin or CC-chemokine receptor 7 and can be found in extralymphoid sites.

LACRIMAR GLANDS

Tear-producing glands in and around the eyelids.

SJOGREN'S SYNDROME

An inflammatory autoimmune disease of the salivary and lacrimar glands that leads to dryness of the mouth and eyes.

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Ley, K., Kansas, G. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat Rev Immunol 4, 325–336 (2004). https://doi.org/10.1038/nri1351

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