Conditions for effective presentation
For a T lymphocyte to recognize an antigen and become activated, the immune synapse must ensure three key tasks are accomplished:
- Elimination of steric (spatial) hindrances that interfere with close intercellular interaction.
- Mobilization of adhesion molecules that form and physically stabilize cell contact.
- Maximum optimization of activating signal transmission inside the T lymphocyte.
Stages of immune synapse formation
The assembly process of the contact zone takes place in three consecutive stages: from cell apposition to the formation of a functionally active structure.
1. Cell polarization Cells approach each other under the influence of chemokines (dendritic cells secrete CCL19 and CCL21, and T helper cells detect them via the CCR7 receptor). The T cell's cytoskeleton rearranges (actin polymerizes), forming leading and trailing edges. Intracellular components orient themselves to facilitate the upcoming contact.
2. Establishment of the primary contact zone The T lymphocyte stops moving — this occurs due to signals from the TCR (T-cell receptor) and the CD4 coreceptor. At this stage, the cells must approach to within 5–15 nm. To prevent any hindrance, large membrane glycoproteins (e.g., CD43 and CD45, which reach up to 40 nm in length) are excluded from the contact zone into the uropod. Interaction at this stage is maintained by adhesion molecules: the T helper cell's LFA-1 integrin binds to the dendritic cell's ICAM-1 receptor.
3. Formation of the mature immune synapse A massive redistribution of molecules takes place: they swap places. Adhesion molecules move to the periphery, while receptor complexes responsible for antigen recognition are drawn into the center. Complete maturation takes from 10 to 20 minutes.
Structure of the mature synapse (“bull's-eye”)
Looking at the formed synapse, it resembles a target. Two distinct zones can be clearly identified:
- Central zone: responsible for transmitting antigenic and costimulatory signals. Here, MHC-peptide complexes (on the antigen-presenting cell) and TCR-CD4 complexes (on the T cell) concentrate, along with costimulatory molecules (CD80/86 and CD28).
- Peripheral zone: forms a ring of adhesion molecules (ICAM and LFA-1 complexes) that mechanically holds the central elements together.
A crucial role in the assembly of the central zone is played by lipid rafts — cholesterol-rich membrane microdomains. It is into these “rafts” that the CD4 coreceptor pulls the TCR molecule, ensuring its incorporation into the synapse. A marker of synapse maturity is the accumulation of the protein kinase C isoform (PKCθ) within the rafts.
The problem of antigen scarcity and serial recognition
For a T cell to be activated, 200–500 pairs of molecules must be triggered within the synapse. However, the surface of a dendritic cell typically bears fewer than 100 MHC complexes with the required (specific) peptide.
This mathematical problem is solved through serial recognition. Each MHC-II–peptide complex works repeatedly: it binds to a TCR molecule, transmits a signal into the cell, after which the spent TCR is internalized, and a new receptor immediately takes its place. In one hour, a single MHC complex interacts with 200 TCR molecules, ensuring accumulation of sufficient signal for activation of naïve cells (which may take up to 20 hours).
Costimulation: the second key to activation
Antigen presentation will not work without additional confirmation. The interaction of the specific TCR receptor with the MHC complex is only the first signal.
The second (accessory) signal is provided by costimulatory molecules. They work in pairs, independently of the primary receptor, but with the aim of amplifying its signal. A classic example: CD80 and CD86 molecules on the antigen-presenting cell bind to the CD28 receptor on the T lymphocyte. If a T cell recognizes an antigen but does not receive a costimulatory signal, it enters a state of specific unresponsiveness — anergy.
Briefly: answers to topical questions
Which intracellular signaling cascades are triggered upon T-cell receptor activation?
Upon T-cell receptor activation, several intracellular signaling cascades are triggered, leading to the formation of NF-AT, NF-κB, and AP-1 transcription factors.
Main signaling pathways:
- Calcium-dependent cascade — activation of phospholipase Cγ1 (PLCγ1) leads to the generation of inositol trisphosphate, mobilization of calcium ions, and activation of calcineurin, which dephosphorylates the NF-AT factor.
- MAP kinase cascade — includes the Rac/JNK branch, the Raf/ERK branch, and the Rac/p38 branch.
- Protein kinase Cθ cascade (PKCθ) — critically important for pathways leading to the formation of NF-κB and AP-1 factors, as well as for the activation of MAP kinase branches.
Which proteins make up the TCR receptor complex?
The T lymphocyte receptor complex includes an antigen-recognizing dimer, signaling complexes, and coreceptors.
Elements of the receptor complex:
- Antigen-recognizing dimer (TCR) — consists of α and β polypeptide chains (in αβTCR) or γ and δ chains (in γδTCR).
- CD3 complex — includes transmembrane polypeptide chains γ, δ, and ε, forming εγ and δε heterodimers.
- CD247 complex — a homodimer of two ζ chains (or a ζη heterodimer) located in the center of the complex.
- Coreceptors — CD4 molecules (on T helper cells) or CD8 molecules (on cytotoxic T lymphocytes) associated with the Lck tyrosine kinase.
Between which cells can immune synapses form, aside from dendritic cells and T helper cells?
Aside from dendritic cells and T helper cells, immune synapses can form between other antigen-presenting and effector cells, as well as their targets.
Types of intercellular interactions resulting in synapse formation:
- Dendritic cell and cytotoxic T lymphocyte (CTL) — for the presentation of an antigenic peptide in complex with MHC-I.
- Macrophage or B lymphocyte and pre-activated T cell — during the course of an immune response.
- Cytotoxic T lymphocyte and target cell — formation of a cytotoxic synapse to execute contact-dependent lysis.
- Natural killer cell (NK cell) and target cell — for the recognition of signs of infection or transformation followed by contact-dependent killing.
The structure of a mature synapse can easily be visualized as a dartboard (“bull's-eye”): the specific signal — antigen-recognizing complexes (TCR and MHC) — hits the very “bull's-eye” (the center), while a ring of adhesion molecules (LFA-1, ICAM) firmly holds them in place at the edges (periphery).
Class and exam questions
Why are CD43 and CD45 molecules cleared from the primary contact zone?
These molecules are very large (about 40 nm in length). They create steric hindrance and prevent cell membranes from drawing close enough (to the 5–15 nm required for signal transmission).
What is the difference between the function of a coreceptor (CD4) and costimulatory molecules (CD28)?
The coreceptor acts as a single unit with the primary T-cell receptor (TCR) and directly participates in MHC recognition. Costimulatory molecules operate independently of the TCR, providing an additional signal that confirms the need for activation.
How does a dendritic cell attract a T lymphocyte prior to synapse formation?
The dendritic cell secretes the chemokines CCL19 and CCL21. Naive T cells bear the CCR7 receptor, which they use to detect this chemical gradient and move toward the dendritic cell.
What else to study on this topic
- Intracellular molecular cascade during T-cell polarization
- Dynamics and composition of membrane lipid rafts
- Differences in synapse formation during antigen presentation to cytotoxic (CD8+) T lymphocytes
- The role of adaptor proteins (LAT) and intracellular kinases (Lck, ZAP-70) in signal transduction
- Influence of TCR–(MHC–peptide) complex half-life on the strength of the immune response
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