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Tissue-tropic effector T cells: generation and targeting opportunities

Key Points

  • Naive T cells circulate mainly through secondary lymphoid organs and the spleen and are largely excluded from extralymphoid tissues. However, once activated in secondary lymphoid organs, a subset of these T cells become effector T cells and gain the ability to enter a wide range of extralymphoid tissues.

  • Effector T-cell subsets display preferential tropism for different extralymphoid tissues, a process that is regulated by their expression of distinct sets of tissue-homing receptors.

  • The panel of homing receptors that are induced on responding T cells depends on the lymph node in which activation takes place. So, T cells activated in intestinal lymph nodes acquire homing receptors for intestinal tissues, whereas T cells activated in skin-draining lymph nodes acquire homing receptors for the skin.

  • Dendritic cells are necessary and sufficient for the induction of tissue-homing receptors on T cells, and therefore have a crucial role in the generation of tissue-tropic effector T-cell subsets.

  • Retinoic-acid receptor signalling in T cells is important for the induction of the gut-homing receptors CC-chemokine receptor 9 (CCR9) and α4β7-integrin.

  • Dendritic cells are imprinted with the ability to induce distinct sets of tissue-homing receptors on T cells before they enter the draining lymph nodes.

Abstract

The localization of effector T cells to extralymphoid tissues is crucial for the generation of an effective immune response, but it also underlies many autoimmune and inflammatory disorders. Recent studies have highlighted a central role for draining lymph nodes and environmentally imprinted dendritic cells in the generation of tissue-tropic effector T cells. Here, I outline our current understanding of the mechanisms that regulate the generation and localization of tissue-tropic effector T cells, and the potential ways in which these pathways can be exploited for immunotherapeutic purposes.

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Figure 1: Circulation of naive and effector T-cell populations.
Figure 2: T-cell entry into lymphoid and extralymphoid tissues is a multistep process coordinated by selective expression of tissue-homing receptors.
Figure 3: Generation of tissue-tropic effector T-cell subsets and their localization to extralymphoid tissues.
Figure 4: Dendritic cells induce expression of tissue-homing receptors on T cells following their priming in regional lymph nodes.
Figure 5: The role of CD103+ dendritic cells in the generation of gut-tropic effector T cells.

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Acknowledgements

I thank all present and former colleagues and collaborators for their contributions to this work and in particular B. Johansson-Lindbom, F. Ivars and C. Johansson for their valuable comments during the preparation of this manuscript. I also apologize to those researchers in the field whose important contributions I have been unable to cite because of space constraints. This work was supported by grants from the Swedish Medical Research Council, the Wellcome Trust, the Crafoordska, Österlund, Åke Wiberg, Richard and Ruth Julins, Nanna Svartz and Kocks foundations, the Royal Physiographic Society, and the Swedish foundation for Strategic Research 'Microbes and Man' and INGVAR II programmes.

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Glossary

Gut-associated lymphoid tissue

Lymphoid structures and aggregates associated with the intestinal mucosa.

B-cell follicle

An aggregate of B cells in lymphoid tissues. It contains naive B cells, as well as activated, proliferating and maturing B cells in germinal centres. B-cell follicles are contiguous with T-cell zones.

Efferent lymph vessels

Lymphatic vessels that transport interstitial fluid and immune cells out of lymph nodes.

Thoracic duct

The major lymphatic vessel that collects lymph from the lower limbs, abdomen, chest and pelvis and returns it to the circulation by the internal jugular and subclavian veins.

Ulcerative colitis

An inflammatory bowel disease characterized by chronic inflammation of the colon.

SAMP1/yit mice

A mutant mouse strain that spontaneously develops a chronic intestinal inflammation that is mainly localized in the terminal ileum.

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

Delayed-type hypersensitivity

A cell-mediated immune response that is evoked following antigen administration in the skin.

Chancroid

Sexually transmitted disease that is caused by the Gram-negative bacterium Haemophilus ducreyi and is characterized by necrotizing genital ulceration.

Pertussis toxin

Pertussis toxin blocks Gαi-coupled receptor signalling (including chemokine-receptor signalling) by catalysing ADP ribosylation of Gαi.

Inguinal lymph node

The inguinal lymph nodes are situated in the upper thigh near the groin and receive draining lymph from cutaneous tissue of the lower extremities.

Peyer's patches

Specialized lymphoid follicles that are localized in the submucosa of the small intestine and appendix.

Langerhans cells

Professional antigen-presenting dendritic cells that are localized in the skin epidermis.

Atopic dermatitis

A common skin-associated chronic hypersensitivity disorder, the aetiology of which remains poorly understood, but in which responsible allergens can occasionally be identified.

Allergic contact dermatitis

Cutaneous inflammatory condition caused by a T-cell-mediated hypersensitivity to defined allergens.

Afferent lymph vessels

Lymph vessels that drain interstitial fluid and immune cells (mainly dendritic cells and memory lymphocytes) from tissues to the draining lymph nodes.

Non-obese diabetic (NOD) mice

An inbred strain of mice that spontaneously develop T-cell-mediated autoimmune diabetes.

Primary sclerosing cholangitis

Chronic liver disease that is caused by progressive inflammation-mediated destruction of the hepatic bile ducts. The disease is of unknown aetiology and can develop as an extra-intestinal complication of inflammatory bowel disease.

Parabiotic mice

Surgically joined mice that share a common blood circulation.

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Agace, W. Tissue-tropic effector T cells: generation and targeting opportunities. Nat Rev Immunol 6, 682–692 (2006). https://doi.org/10.1038/nri1869

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