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  • Review Article
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Tuning immune responses: diversity and adaptation of the immunological synapse

Nature Reviews Immunology volume 5, pages 532–545 (2005)Cite this article

Key Points

  • The onset and regulation of a specific immune response results from communication between T cells and antigen-presenting cells (APCs), which form a molecular cell–cell contact that is known as the immunological synapse.

  • Initially, the immunological synapse was viewed as a stereotypical adhesion and signalling device with a defined molecular structure and signalling processes.

  • However, as we discuss in this article, T cell–APC interactions comprise a diverse range of contact modes and distinct molecular arrangements.

  • The diversity of interaction modes might define a molecular code, which uses the different timing, spacing and molecular compositions of signalling platforms to determine the outcome of T cell–APC interactions.

Abstract

The onset and regulation of a specific immune response results from communication between T cells and antigen-presenting cells (APCs), which form molecular interactions at the site of cell–cell contact — and this is known as the immunological synapse. Initially, the immunological synapse was viewed as a stereotypical adhesion and signalling device with a defined molecular structure and signalling processes. However, as we discuss here, T-cell–APC interactions comprise a diverse range of contact modes and distinct molecular arrangements. These diverse interaction modes might define a molecular code, in which the differences in timing, spacing and molecular composition of the signalling platform determine the outcome of T-cell–APC interactions.

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Figure 1: Morphology and phases of interaction between T cells and antigen-presenting cells.
Figure 2: Tuning model of contact mode and diversity, as determined by antigen-presenting-cell type, environment and antigen load.
Figure 3: Diversity of molecular-interaction zones of the immunological synapse.
Figure 4: Molecular topography of the immunological-synapse platform.
Figure 5: Different modes of interaction between T cells and antigen-presenting cells, and the outcomes of these interactions.

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Acknowledgements

We acknowledge M. Jobberger for carrying out scanning electron microscopy and T. Stradal, B. Schraven and M. Davis for helpful comments and discussion. This work was supported by grants from the Deutsche Forschungsgemeinschaf (Germany) to P.F. and M.G., and from the Dutch Cancer Society to A.Th.d.B.

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Authors and Affiliations

  1. Rudolf Virchow Center for Experimental Biomedicine and Department of Dermatology, University of Würzburg, Würzburg, 97080, Germany

    Peter Friedl & Annemieke Th. den Boer

  2. German Research Centre for Biotechnology, Braunschweig, 38124, Germany

    Matthias Gunzer

Authors
  1. Peter Friedl
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  2. Annemieke Th. den Boer
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  3. Matthias Gunzer
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Correspondence to Peter Friedl.

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DATABASES

Entrez Gene

AKT

CD2

CD3ζ

CD11a

CD28

CD45

CD80

CTLA4

ICAM1

IFN-γR

IL-4R

LAT

LCK

LFA1

PKC-θ

talin

ZAP70

FURTHER INFORMATION

Intravital microscopy of DC networks

Imaging of T-cell interactions with different APCs

Intravital microscopy of T-cell activation by DCs in lymph nodes

Glossary

UROPOD

The posterior tail of migrating amoeboid cells. It is rich in filamentous actin, microtubules, and cytoskeletal adaptor proteins (such as ezrin and moesin), as well as adhesion molecules (such as CD43 and CD44) and lipid rafts.

LEADING LAMELLIPODIUM

An actin-rich membrane protrusion that extends, retracts and generates physical traction towards the underlying substrate in the process of cell migration.

BLAST

An immune cell in a proliferating state, as shown by an enlarged cytoplasm and nucleus (assessed by blood smears or flow cytometry). A T lymphoblast has entered the S (synthesis) and G2 (gap 2) phases of the cell cycle, and under activating conditions, it develops into an effector T cell or a memory T cell. Under tolerizing conditions, a T lymphoblast can either become anergic or undergo apoptosis through activation-induced cell death.

AGONIST PEPTIDE

A peptide that mimics cognate antigen and results in T-cell activation and proliferation. Agonistic activity is often, but not always, associated with high-affinity and/or avidity binding of TCR to peptide–MHC complexes.

ANTAGONIST PEPTIDE

A peptide that prevents T-cell activation by cognate antigen, either by competition for TCR sites or by active delivery of negative signals.

PERIPHERAL INTERSTITIAL TISSUES

Immune cells constitutively enter and migrate through all parenchymatous tissues and organs (which are composed of a loose fibrillar extracellular matrix and the parenchymal cells contained within it), including the skin, kidneys, thyroid gland, liver and lungs. Under non-inflammatory conditions, regions that are excluded from T-cell trafficking are the bone, brain, vitreous body of the eye and parts of the testes.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A technique that is used to measure protein–protein interactions either by microscopy or flow cytometry. Proteins fused to cyan, yellow or red fluorescent proteins are expressed and assessed for interaction by measuring the energy transfer between fluorophores, which can only occur if proteins physically interact. FRET can also be used to examine the activation state of certain proteins if their activation results in a change in the conformation of the protein.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). A sequence that is present in the cytoplasmic domains of the invariant chains that are associated with various cell-surface immune receptors, such as the T-cell receptor, the B-cell receptor, the receptor for IgE (FcεR) and natural-killer-cell activating receptors, as well as in some signalling molecules that are immediately downstream. Following phosphorylation of the tyrosine residue, ITAMs function as docking sites for SRC homology 2 (SH2)-domain-containing tyrosine kinases and adaptor molecules, thereby facilitating intracellular-signalling cascades.

SRC-HOMOLOGY-2 DOMAIN

(SH2 domain). A protein domain that is commonly found in signal-transduction molecules. It specifically recognizes phosphotyrosine-containing peptide sequences in proteins.

PLECKSTRIN-HOMOLOGY DOMAIN

A protein–lipid interaction domain that usually consists of 100 amino-acid residues. These domains have little overall sequence homology but have conserved motifs and tertiary structure. They are thought to be involved in the anchoring of proteins to the membrane and have been found to bind the following: phospholipids (including phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-3,4,5-trisphosphate), proteins (including the β- and γ-subunit of heterotrimeric G proteins), and phosphorylated serine or threonine residues.

LIPID RAFT

An area of the plasma membrane that is rich in cholesterol, glycosphingolipids, several signalling proteins — such as SRC-family kinases, RAS, LAT (linker for activation of T cells) and PAG (protein associated with glycolipid-enriched microdomains) — and glycosylphosphatidylinositol-anchored proteins. These domains are also known as glycolipid-enriched microdomains (GEMs) and detergent-insoluble glycolipid-enriched membranes (DIGs).

SUPRAMOLECULAR ACTIVATION CLUSTER

(SMAC). A membrane region that is enriched in (clustered) TCR, adhesion molecules and/or signalling molecules, as detected by fluorescence microscopy. SMACs are thought to be focalized regions of receptor–ligand interaction and signal transduction. Their known size ranges from ∼150 nm to several millimetres in diameter. Because of the limited resolution of light microscopy, neighbouring aggregates of less than ∼150 nm cannot be discriminated as individual objects and therefore appear as 'diffusely' distributed. The number, size and function of very small clusters therefore remains unknown.

GRANZYMES

Secreted serine proteases that enter target cells by a receptor-mediated endocytic pathway, then cleave and activate intracellular caspases, leading to target-cell apoptosis.

PERFORIN

A secreted protein that supports the cytotoxic function of granzymes in the target cell. After being internalized by the target cell, perforin disrupts the endosomal membrane and mediates the transport of granzymes into the cytoplasm.

NEGATIVE SELECTION

A step in the process of T-cell differentiation in the thymus. T cells that express T-cell receptors with high affinity for self-antigens are eliminated from the repertoire by apoptosis after recognition of their target antigen presented by thymic medullary epithelial or dendritic cells.

OPTICAL REPORTER ASSAY

T cells that express a fluorescent protein (such as green fluorescent protein) under the control of a promoter of a gene involved in T-cell-receptor activation fluoresce if activation occurs. Useful reporter constructs for determining activation are the interleukin-2 (IL-2) promoter, for initial activation, and the IL-4 or interferon-γ promoter, for T-cell effector function.

POSITIVE SELECTION

A step in the process of T-cell differentiation in the thymus. T cells that express T-cell receptors with moderate to high affinity for self-antigens receive a survival signal and continue to develop towards becoming double positive (CD4+CD8+) T cells. Positive selection occurs through antigens presented by resident stromal cells and dendritic cells in the thymic cortex and is followed by negative selection.

HOMEOSTASIS

The maintenance of relatively stable numbers of peripheral T cells. Naive CD4+ and CD8+ T cells recirculate between the blood and secondary lymphoid organs, where they receive survival signals.

TH1-CELL PHENOTYPE

(T–helper-1 cell phenotype). A T helper cell that mainly secretes interleukin-2 and interferon-γ (IFN-γ). These cells therefore support cell-mediated immune responses, such as activation of cytotoxic T cells, IFN-mediated killing of virus-infected cells and activation of the monocyte/macrophage system.

TWO-PHOTON INTRAVITAL MICROSCOPY

Laser-scanning microscopy that uses pulsed infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. The main advantage is deep tissue penetration of the infrared light, owing to the low level of light scattering within the tissue.

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Friedl, P., den Boer, A. & Gunzer, M. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat Rev Immunol 5, 532–545 (2005). https://doi.org/10.1038/nri1647

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