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Migration of T Cells in Vivo: Molecular Mechanisms and Clinical Implications

Jürgen Westermann, MD; Britta Engelhardt, MD; and Jörg C. Hoffmann, MD
[+] Article and Author Information

From Medizinische Universitat zu Lübeck, Lübeck; Max-Planck Institut für physiologische und klinische Forschung, W.G. Kerckhoff-Institut, Bad Nauheim; and Medizinische Klinik, Universitä tskliniken des Saarlandes, Homburg/Saar, Germany.


Acknowledgments: The authors thank colleagues in the department of functional and applied anatomy for their continuous support, especially K. Bankes, I. Dressendörfer, S. Lopez-Kostka, and F. Weidner. They also thank A. Gebert, B. Lüttig, R. Pabst, R. Schwinzer, and T. Tschernig (Medical School of Hannover, Germany) for critical comments on the manuscript; M. Peter for help in preparing the figures; and S. Fryk for help with the English language.

Grant Support: By the Deutsche Forschungsgemeinschaft (SFB 244 A7 and We 1175/4-3).

Requests for Single Reprints: Jürgen Westermann, MD, Institute of Anatomy, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; e-mail, westermann@anat.mu-luebeck.de.

Current Author Addresses: Dr. Westermann: Institute of Anatomy, University of Lübeck, Ratzeburger Allee 160, 23538 Lü beck, Germany.

Dr. Engelhardt: Abteilung für Vaskuläre Zellbiologie, Max-Planck-Institut, Parkstrasse 1, D-61231 Bad Nauheim, Germany.

Dr. Hoffmann: Innere Medizin II, Universitätskliniken des Saarlandes, D-66421 Homburg, Germany.


Ann Intern Med. 2001;135(4):279-295. doi:10.7326/0003-4819-135-4-200108210-00013
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T cells play an important role in the pathogenesis of chronic and autoimmune inflammatory diseases. They are found in high numbers in involved tissues, such as the lamina propria of the gut in patients with Crohn disease. Modifying T-cell number and function may therefore be of therapeutic value.

In principle, two mechanisms may be responsible for the development of such T-cell infiltrates: 1) an increased rate of T-cell immigration into involved tissues or 2) an increased proliferation rate, decreased T-cell death (apoptosis) rate, and prolonged retention of T cells already in the tissue. Based on the theory that T cells selectively target affected tissues through organ-specific adhesion-molecule pathways, current anti-adhesion-molecule therapy aims to interfere selectively with T-cell entry to stop tissue damage.

However, the traffic of labeled T cells in unmanipulated animals shows that the entry of T-cell subsets into tissues is not organ-specific, even under conditions of differing adhesion molecule and chemokine receptor expression. In contrast, within various tissues, both movement and survival of T-cell subsets differ considerably. These observations suggest that the differential expression of adhesion molecules and chemokine receptors on T cells serves at least two functions in vivo. First, during migration of T cells out of the bloodstream, the different adhesion-molecule pathways provide redundancy, which guarantees that T-cell subsets are able to enter the different tissues in sufficient numbers (security). Second, adhesion molecules and chemokine receptors mediate T-cell interactions within the tissue that are characteristic for each subset and each microenvironment and determine the nature of the ensuing immune response (selectivity). Shifting the focus of anti-adhesion-molecule therapy toward the T cells in diseased tissue may lead to new treatment options.

Figures

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Figure 1.
Different L-selectin expression on T cells does not lead to organ-specific entry in vivo.+HEV(27)(27)(28, 29)(27)

Naive and memory CD4 T cells both localize in high endothelial venules ( ) of peripheral lymph nodes and enter the T-cell area in similar numbers . Within the tissue, memory T cells may reach the exit compartment of the lymph node, the medulla, faster and exit more quickly than naive T cells . T-cell subsets were isolated from rat thoracic duct, injected into the unmanipulated host, and analyzed as described . L-selectin expression is determined by flow cytometry and indicated as fluorescence intensity (arbitrary channels ranging from 1 [lowest intensity] to 1024 [highest intensity]). Light blue = naive T cells; dark blue = memory T cells. The bars indicate the number of injected T cells per area of the respective compartments at various times after injection. Error bars represent standard deviations.

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Figure 2.
Tissue migration of T cells that do not express the usual adhesion molecules.leftright(51)

In vitro ( ), memory T cells expressing low levels of L-selectin are not able to bind under flow conditions to high endothelial venules of peripheral lymph nodes and are therefore not able to transmigrate. In vivo ( ), platelets may adhere to the endothelium and offer P-selectin as an additional ligand . Memory T cells expressing the respective receptor now bind to the platelets and indirectly to the high endothelial venules. Although L-selectin is not expressed or is expressed only at very low levels on memory T cells, in vivo those T cells are in principle able to migrate into peripheral lymph nodes.

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Figure 3.
Migration pattern of resting and activated T cells in vivo.white barsgray bars54511255556

Most resting T cells ( ) are found in lymphoid organs, such as lymph nodes and spleen, 1 day after injection into rats. At the same time, activated T cells ( ) are found in reduced numbers in lymph nodes and spleen and in higher numbers in many nonlymphoid organs. The lymphoid organs still receive many activated T cells. Rat thoracic duct lymphocytes (consisting mainly of T cells [ ]) were labeled with Cr (resting T cells) or I (activated T cells) and injected into the rat tail vein. One day later, the radioactivity of the different tissues was determined and was expressed as the percentage of the injected dose (data derived from reference and from reference for the small intestine).

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Figure 4.
Expression of adhesion molecules on many cell types within the tissue. Top.HEVarrowsBottom.arrows

Intercellular adhesion molecule-1 is expressed on the endothelium of a high endothelial venule ( ) of a rat peripheral lymph node ( ) (alkaline antialkaline phosphatase technique, hemalum counterstain; original magnification, ×100). Intercellular adhesion molecule-1 is expressed not only on the endothelium of HEV ( ) but also on many other cell types within the T- and B-cell area of the lymph node. The broken line encloses the area magnified in the top panel. The insert shows a control staining of the consecutive lymph node section using an irrelevant antibody (alkaline antialkaline phosphatase technique, hemalum counterstain; original magnification, ×20). co = cortex, B-cell area; gc = germinal center; pa = paracortex, T-cell area.

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Figure 5.
Roles of adhesion molecules in T-cell migration and function. Top.leftmiddlemiddlerightBottom.leftmiddlemiddleright

Blood vessel. Adhesion molecules quickly decelerate ( ) the velocity of the T cell in the blood ( ), then mediate firm adherence to the endothelium against shear forces and facilitate subsequent transmigration ( ). Multiple adhesion-molecule pathways at the entry site provide the necessary redundancy, guaranteeing T-cell entry under these harsh conditions even if one adhesion molecule does not function (adhesion molecules secure entry). To prevent T-cell entry for therapeutic purposes, more than one adhesion molecule would need to be blocked ( ), reducing entry not only into the target organ but also into many other tissues (side effects probable). Tissue. T cells migrate slowly and for long periods ( ). Adhesion molecules on T cells interact with other cells and the extracellular matrix to mediate T-cell movement ( ). Adhesion molecules are also involved in the regulation of antigen presentation, co-stimulation, and proliferation ( ), which largely determines whether an immune response starts, its quality, and whether it stops or becomes chronic (adhesion molecules select interactions within the tissue). Specific interference with these interactions ( ) might be a particularly promising approach to the treatment of T-cell-mediated diseases (selectivity for target organ possible).

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