Immunological synapse: structures, molecular mechanisms and therapeutic implications in disease

Abstract

The immunological synapse (IS) serves as the fundamental architectural framework for direct interactions and secretory crosstalk between immune cells, as well as between immune cells and other cells. Its dysregulation is thought to be a key underlying cause of immune evasion or inflammation observed in various diseases, including tumors and infections. Numerous recent studies have addressed key signaling mechanisms and reported novel targets related to IS, further broadening our understanding of its function and regulatory factors. However, a comprehensive review that highlights recent progress and consolidates past knowledge is still lacking. In this study, we delineated the pre- and postsynaptic structures constituting the IS between T cells, natural killer (NK) cells, dendritic cells (DCs), and macrophages. We also detail the specific signaling mechanisms and pathways that modulate the formation and disassembly of the IS, including cytoskeletal remodeling, membrane reshaping, integrin signaling, and force transduction. Following these experimental findings, we systematically review the central roles of IS in maintaining homeostasis and health and outline various diseases arising from IS disorders. Finally, we thoroughly explore targets and treatments related to IS on the basis of preclinical evidence and clinical trials, with the aim of providing further investigatory and therapeutic insights for researchers and clinicians.

Fig. 1

History of research on immunological synapses. This figure illustrates the major discoveries related to immunological synapses (IS), from their initial formal reporting and roles in diseases to the identification of key regulatory mechanisms and treatment inspirations. It highlights the progress made over time in understanding the structure and regulatory mechanisms of the IS during the 2000s. With the advent of new technologies, the direct observation of IS images both in vivo and in vitro in the 2010s has significantly enhanced our understanding of IS and has influenced clinical treatment approaches. Image created with BioRender (https://biorender.com/)

Fig. 2

The IS interface between T cells and APCs. a When T cells bind to APCs, they form a stimulatory synapse characterized by three concentric bullseye-like structures on the T cell surface. The cSMAC contains TCRs bound to pMHC complexes and signaling molecules. The pSMAC and dSMAC contain adhesion molecule pairs. When pMHC forms a complex with TCR in the dSMAC, it can induce the formation of microclusters, which will pull the distal pMHC-TCR complexes to move to the cSMAC. b When TCR on CTLs are activated by pMHC complexes, they establish a lytic synapse. Through a contractile actin meshwork rich in myosin, CTLs exocytose lytic granules to release granzymes and perforin toward the target cell. Image created with BioRender (https://biorender.com/)

Fig. 3

Endocytosis and ectocytosis of T cells. T cells downregulate surface TCR expression and downstream signaling upon activation primarily to avoid sustained overstimulation and timely disengagement from target cells either via endocytosis or exocytosis. These are two topologically opposite processes coordinated by the sequential recruitment of ecto- and endocytic adapters (HRS and STAM2). a EPN1 recruits clathrin to remaining TCR microclusters to enable trans-endocytosis of pMHC-TCR conjugates from the APCs through membrane invagination and vesicle formation. b TCR sheds from membranes via the coordination of clathrin recruitment and DAG signaling activation and then enters into outer bodies to mediate direct ectocytosis from the plasma membrane (called synaptic ectosomes). Image created with BioRender (https://biorender.com/)

Fig. 4

Force signaling transduction of lymphocytes. a Activation of three lymphocyte subtypes under various external stimuli; b Conformational changes in the intracellular domain of the TCR upon mechanical stimuli. In the resting state, CD3ε and CD3ζ are inserted into the membrane through electrostatic interactions, preventing their phosphorylation by Lck. In the open state, ITAM fully dissociates from the plasma membrane. The Tyr residues within ITAM are phosphorylated by Lck, recruiting downstream signaling molecules such as Zap70. The PRS region recruits Nck, leading to cytoskeletal remodeling to accommodate T cell activation. Image created with BioRender (https://biorender.com/)

Fig. 5

Immunological synapse in various diseases. Dysregulation of immunological synapses is involved in various human diseases. For instance, it is necessary to maintain normal Pre/Post-synaptic T cells to recognize and kill tumor cells. Bacteria and viruses employ various mechanisms to inhibit IS assembly and downstream signal transduction. Viruses can even establish viral synapses to facilitate cell-to-cell infection, thereby evading immune cell-mediated killing and causing infections. However, excessively strong IS can lead to the overactivation of cells, particularly T cells, resulting in excessive cytokine secretion and the development of non-infectious inflammation. For example, an overabundance of IL-17 can trigger conditions such as psoriasis and Crohn’s disease. Overproduction of autoantibodies by B cells can lead to nephritis and rheumatoid arthritis, while overactivation of microglia can result in the phagocytosis of normal neurons, contributing to the development of Alzheimer’s disease and Parkinson’s disease. Additionally, there are therapeutic interventions targeting the formation of IS, such as those used for GVHD and allergic asthma. Image created with BioRender (https://biorender.com/)

Fig. 6

Immunological synapse in modulating tumor immune surveillance and immunoevasion. The yin and yang struggle between T cells and tumor cells at the IS. a T cells form an immune synapse with tumor cells, and perforin creates pores in the tumor cell membrane, allowing granzymes to enter the target cell and induce apoptosis. b T cell activation depends on the influx of Ca²⁺ and the activation of NF-AT. c Diverse TCR-expressing CTLs can bind to the same tumor cell, resulting in a cumulative cytotoxic effect. d After attacking, the tumor cell cytoskeleton contracts, prompting the CTL to separate the apoptotic tumor cell, thereby mediating the killing of other tumor cells. e After the tumor cell membrane is perforated, ESCRT is recruited to the contact site and mediates membrane repair. f Tumor cells utilize Ca²⁺ for membrane repair to prevent immune-mediated destruction. g CDC42 and N-WASP remodel the tumor cell cytoskeleton to resist NK cell-mediated killing. h Dying tumor cells still form an IS with CTLs, continuously providing antigenic stimulation signals that induce T cell exhaustion. Image created with BioRender (https://biorender.com/)