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Gamma delta T cells are a unique subset of T cells that play a crucial role in various immune responses and immunopathologies. The γδ T cell receptor (TCR) is produced by γδ T cells and is able to recognize a wide range of antigens independently of the major histocompatibility complex. γδ TCR binds to the CD3 subunit and initiates T cell activation, which has great potential in immunotherapy.
2024年4月24日，西湖大学周强及宿强共同通讯在Nature 在线发表题为“Structures of human γδ T cell receptor-CD3 complex”的研究论文，该研究报道了两种典型人类Vγ9vδ2和Vγ5vδ1 TCR-CD3复合物的结构，揭示了依赖于Vγ使用的两种不同的组装机制。
T cells are an important component of the vertebrate adaptive immune system, defending against invading pathogens and malignant cells. Human T lymphocytes can be divided into αβ and γδ T cells based on the expression of αβ or γδ T cell receptors (TCRs). Unlike traditional alpha-beta T cells, γδ T cells have adaptive and innate immune properties that constitute a unique population of lymphocytes. Gamma delta T cells provide a broad protective immune response to a variety of infections and sterile stresses, including cytomegalovirus and Mycobacterium tuberculosis infections, tumor growth, and tissue dysregulation. γδ TCR is a heterodimer composed of TCR γ and TCR δ chains, discovered in the mid-80s of the 20th century. Similar to αβ TCR, the TCRγ/TCR δ chain undergoes somatic recombination of variable (V), diversity (D), and junction (J) gene fragments, resulting in substantial sequence diversity. However, the Vγ and Vδ spectra in humans are much smaller than those of TCRα/TCRβ. The TCRγ locus contains 6 functional V gene fragments (Vγ2, 3, 4, 5, 8, 9), while the TCRδ locus contains only 3 true V gene fragments (Vδ1, 2, 3). Other Vδ fragments, such as Vδ5, are derived from specific Vα genes that are not commonly used in δ-strand rearrangements. In addition to the differences in the V gene pool, there are also differences in antigen recognition between γδ TCRs and αβ TCRs. αβ TCRs primarily recognize peptide antigens presented by major histocompatibility complex (MHC) molecules, while γδ TCRs can recognize multiple types of antigens in MHC-independent ways. For example, Vγ9vδ2 TCRs respond to small phosphorylated non-peptide antigens, such as hydroxymethylbutyl-2-enylpyrophosphate (HMBPP) and prenylpyrophosphate (IPP), which are produced by cellular pathogens and cancer, respectively. The recognition of these phosphoantigens by Vγ9vδ2 TCRs is dependent on butyrophilin (BTN) 2A1 and BTN3A1. Some specific Vγ5Vδ1 TCRs, such as 9C2 γδ TCR, can recognize glycolipid antigens presented by CD1d molecules.
人Vγ9Vδ2和Vγ5Vδ1 TCR-1100 CD3复合物（Credit: Nature）
In humans, the TCRγ/TCRδ chain binds to three CD3 dimer subunits: CD3εγ/CD3εδ/CD3ζ to form an octamer γδ TCR-CD3 complex. Each TCRγ or TCRδ contains an extracellular domain (ECD) with a Vγ/Cγ or Vδ/Cδ domain, a membrane-proximal linker peptide (CP), a transmembrane helix (TM), and a short cytoplasmic tail. Similarly, CD3γ, CD3δ, and CD3ε contain ECD, CP, TM helice, and intracellular immune receptor tyrosine activation motifs (ITAM), respectively. In contrast, CD3ζ lacks ECD and has one TM helix and three intracellular ITAMs. Upon binding to antigen, the γδ TCR-CD3 complex triggers phosphorylation of ITAMs in the cytoplasmic tail of the CD3 subunit, initiating downstream events. The γδ TCR-CD3-mediated effector function and its unique properties make it an attractive target for cancer immunotherapy. The study demonstrates the cryo-electron microscopy (cryo-EM) structure of two ligand-free human Vγ9vδ2 and Vγ5vδ1 TCR-CD3 complexes, revealing two different assembly mechanisms that rely on the use of a specific Vγ subset. The Vγ9vδ2 TCR-CD3 complex is a monomer with considerable conformational flexibility in TCRγ/TCRδ extracellular domains (ECDs) and linked peptides (CPs). The length of CPs regulates ligand binding and T cell activation. In addition, cholesterol-like molecules are wedged into the transmembrane region and exert an inhibitory effect on TCR signaling. The Vγ5vδ1 TCR-CD3 complex exhibits a dimeric structure, in which two protopolymers are nested back-to-back by the Vγ5 domain of the TCR ECD. Biochemical and biophysical analyses further confirmed the structure of the dimer. Importantly, the dimeric form of Vγ5vδ1 TCR is essential for T cell activation. These findings reveal the organizational principles of the γδ TCR-CD3 complex, provide insights into the unique properties of γδ TCR, and facilitate immunotherapeutic interventions.
Original link https://www.nature.com/articles/s41586-024-07439-4
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文章来源|“ iNature”
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