T cell antigen recognition: Evolution-driven affinities

Bosselut, Rémy

doi:10.1073/pnas.1916129116

Cited by 11 publications

(9 citation statements)

References 19 publications

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“…In fact, the TCR triggering is strictly connected to the T cell activation, and it is regulated by two main interactions: (i) the interaction between the peptide and the MHC I with the TCR, in the extracellular surroundings [ 2 ]; (ii) the interaction of the CD3 chains with the TCR in the intracellular environment [ 3 ] ( Figure 1 ). The ability of TCR to recognize a huge number of peptides presented by the MHC I ensures a solid defense system from foreign pathogens [ 4 ]. MHC I is a protein complex formed by an α chain, which hosts the binding site for a nine/ten residue-long peptide, and a non-covalent bound β 2 microglobulin [ 5 ] ( Figure 1 and Figure 2 a).…”

Section: Introductionmentioning

confidence: 99%

The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States

Alba

D’Abramo

2022

Cells

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The machinery involved in cytotoxic T-cell activation requires three main characters: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3 complex, a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied by means of both experimental and computational models, giving a contribution in understanding the complexity of the TCR triggering. Nevertheless, a detailed study of the structural and dynamical characterization of the full complex (pMHC:TCR:CD3 complex) is still missing due to a lack of structural information of the CD3-chains arrangement around the TCR. Very recently, the determination of the TCR:CD3 complex structure by means of Cryo-EM technique has given a chance to build the entire system essential in the activation of T-cells, a fundamental mechanism in the adaptive immune response. Here, we present the first complete model of the pMHC interacting with the TCR:CD3 complex, built in a lipid environment. To describe the conformational behavior associated with the unbound and the bound states, all-atom Molecular Dynamics simulations were performed for the TCR:CD3 complex and for two pMHC:TCR:CD3 complex systems, bound to two different peptides. Our data point out that a conformational change affecting the TCR Constant β (Cβ) region occurs after the binding to the pMHC, revealing a key role of this region in the propagation of the signal. Moreover, we found that TCR reduces the flexibility of the MHC I binding groove, confirming our previous results.

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Section: Introductionmentioning

confidence: 99%

The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States

Alba

D’Abramo

2022

Cells

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“…In this sense, the expression of TCRs is clonotypic since one T cell expresses a single TCR specificity that is determined by both the antigen peptide and the MHC determinants. TCR diversity, which is generated by mechanisms of genomic rearrangement, and the fact that MHC molecules are highly polymorphic allow organisms to counteract pathogen evasion of T cell responses [89]. While TCR is the major CTL marker, the glycoproteins CD3, CD8 and CD57 are other important markers which bind MHC molecules [89].…”

Section: Receptorsmentioning

confidence: 99%

“…TCR diversity, which is generated by mechanisms of genomic rearrangement, and the fact that MHC molecules are highly polymorphic allow organisms to counteract pathogen evasion of T cell responses [89]. While TCR is the major CTL marker, the glycoproteins CD3, CD8 and CD57 are other important markers which bind MHC molecules [89]. The structure and function of immunoglobulin M (IgM), the classic TCRs (αβ chains) and MHC class II are conserved in jawed vertebrates from cartilaginous and bony fishes, to amphibians, reptiles, birds, and mammals.…”

Section: Receptorsmentioning

confidence: 99%

Evolution of Cellular Immunity Effector Cells; Perspective on Cytotoxic and Phagocytic Cellular Lineages

Mandujano-Tinoco

Sultan

Ottolenghi

et al. 2021

Cells

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The immune system has evolved to protect organisms from infections caused by bacteria, viruses, and parasitic pathogens. In addition, it provides regenerative capacities, tissue maintenance, and self/non-self recognition of foreign tissues. Phagocytosis and cytotoxicity are two prominent cellular immune activities positioned at the base of immune effector function in mammals. Although these immune mechanisms have diversified into a wide heterogeneous repertoire of effector cells, it appears that they share some common cellular and molecular features in all animals, but also some interesting convergent mechanisms. In this review, we will explore the current knowledge about the evolution of phagocytic and cytotoxic immune lineages against pathogens, in the clearance of damaged cells, for regeneration, for histocompatibility recognition, and in killing virally infected cells. To this end, we give different immune examples of multicellular organism models, ranging from the roots of bilateral organisms to chordate invertebrates, comparing to vertebrates’ lineages. In this review, we compare cellular lineage homologies at the cellular and molecular levels. We aim to highlight and discuss the diverse function plasticity within the evolved immune effector cells, and even suggest the costs and benefits that it may imply for organisms with the meaning of greater defense against pathogens but less ability to regenerate damaged tissues and organs.

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“…Two main macrophage lineages are known: first, the macrophages that differentiate from blood-circulating monocytes that arise from bone marrow myeloid progenitor cells and migrate to areas of host injury; and second, those that come from the yolk sac and are resident in tissues [2,3]. Macrophages, dendritic cells and B cells act as professional antigen-presenting cells (APCs) that present antigens and activate T cells via their cluster of differentiation-CD80, CD86, and major histocompatibility complex class II (MHC II)-leading to adaptive immune system activation [4][5][6][7]. Moreover, in addition to their role in phagocytosis, macrophages secrete a number of cytokines that induce immunecell activity and activate a cascade of events during immune response.…”

Section: Introductionmentioning

confidence: 99%

Thymoquinone Effect on Monocyte-Derived Macrophages, Cell-Surface Molecule Expression, and Phagocytosis

et al. 2022

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Macrophages are one of the most important cells in the immune system. They act as links between innate and adaptive immunities. In this study, the aim was to examine thymoquinone effects on the immunological properties of different macrophages. Peripheral blood mononuclear cells were isolated from blood from healthy volunteers by negative selection of monocytes that had been cultured for seven days to differentiate into macrophages. Cells were cultured with or without the presence of thymoquinone (TQ), which was used in two different concentrations (50 μg/mL and 100 μg/mL. Cluster of differentiation 80 (CD80), cluster of differentiation 86 (CD86), and human leukocyte antigen DR isotype (HLA-DR) were measured by flow cytometry, and the secretion of interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) was measured. Cells were also tested for their E. coli phagocytosis abilities. The data showed that the expression of HLA-DR was significantly higher in cells treated with 100 μL/mL TQ. In addition, IFN-γ concentration increased in the 100 μg/mL TQ-treated cells. The macrophage phagocytosis results showed a significant difference in 50 μg/mL TQ-treated cells compared to the controls. TQ may enhance the immunological properties of macrophages during the early stages of innate immunity by activating phagocytosis ability and by increasing the expression of HLA-DR and the secretion of IFN-γ, which may enhance the antigen-presentation capabilities of macrophages.

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T cell antigen recognition: Evolution-driven affinities

Cited by 11 publications

References 19 publications

The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States

The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States

Evolution of Cellular Immunity Effector Cells; Perspective on Cytotoxic and Phagocytic Cellular Lineages

Thymoquinone Effect on Monocyte-Derived Macrophages, Cell-Surface Molecule Expression, and Phagocytosis

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