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Dynamics of membrane trafficking downstream of B and T cell receptor engagement: impact on immune synapses.

Yuseff MI, Lankar D, Lennon-Duménil AM - Traffic (2009)

Bottom Line: The onset of an adaptive immune response requires the activation of T and B lymphocytes by antigen-presenting cells, through a specialized form of intercellular communication, known as the immunological synapse (IS).In this review, we highlight the similarities that determine B and T cell activation, focusing on immune receptor downstream signaling events that lead to synapse formation.We stress the notion that polarization of T and B lymphocytes characterized by global changes in cytoskeleton and membrane trafficking modulates synapse structure and function, thus determining lymphocyte effector functions and fate.

View Article: PubMed Central - PubMed

Affiliation: INSERM U932, Institut Curie, 75005 Paris, France.

ABSTRACT
The onset of an adaptive immune response requires the activation of T and B lymphocytes by antigen-presenting cells, through a specialized form of intercellular communication, known as the immunological synapse (IS). In B lymphocytes the IS promotes efficient recognition and acquisition of membrane-bound Ags, while in T cells, it modulates the T cell response upon exposure to peptide-major histocompatibility complexes. In this review, we highlight the similarities that determine B and T cell activation, focusing on immune receptor downstream signaling events that lead to synapse formation. We stress the notion that polarization of T and B lymphocytes characterized by global changes in cytoskeleton and membrane trafficking modulates synapse structure and function, thus determining lymphocyte effector functions and fate.

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Later stages of the IS in B and T cells: vesicle trafficking and changes in polarization and membrane morphology determine effector functionsLater stages of lymphocyte activation leads to a dynamic reorganization of the membrane interface characterized by the presence of two concentric regions: cSMAC, where immune-engaged receptors are found and a pSMAC containing adhesion molecules, such as LFA-1 interacting with ligands on the surface of the APC. A) TCR downstream signaling events drive the polarization of the microtubule network, highlighted by the translocation of the MTOC, toward the IS, a mechanism that serves as a guide for the targeted secretion of cytokines. At the IS, engaged TCRs are internalized from the cSMAC, where they can be recycled to the plasma membrane or targeted for degradation by ubiquitination. B) B cells engaged to membrane-bound Ag leads to its extraction, by a yet undefined mechanism. Ag–BCR complexes are transported by ubiquitin signaling into late-endocytic compartments for processing and the derived peptides are loaded onto MHC class II molecules for further presentation to CD4 T cells. Activated BCR-signaling downstream effectors such as Syk and the Myosin II motor trigger actin cytoskeleton remodeling, promoting an efficient recruitment of MHC class II/Lamp1+molecules toward the Ag−processing compartment. In both schemes, downstream effector molecules control vesicle trafficking and membrane cytoskeleton remodeling, all events dictating lymphocyte effector function.
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fig02: Later stages of the IS in B and T cells: vesicle trafficking and changes in polarization and membrane morphology determine effector functionsLater stages of lymphocyte activation leads to a dynamic reorganization of the membrane interface characterized by the presence of two concentric regions: cSMAC, where immune-engaged receptors are found and a pSMAC containing adhesion molecules, such as LFA-1 interacting with ligands on the surface of the APC. A) TCR downstream signaling events drive the polarization of the microtubule network, highlighted by the translocation of the MTOC, toward the IS, a mechanism that serves as a guide for the targeted secretion of cytokines. At the IS, engaged TCRs are internalized from the cSMAC, where they can be recycled to the plasma membrane or targeted for degradation by ubiquitination. B) B cells engaged to membrane-bound Ag leads to its extraction, by a yet undefined mechanism. Ag–BCR complexes are transported by ubiquitin signaling into late-endocytic compartments for processing and the derived peptides are loaded onto MHC class II molecules for further presentation to CD4 T cells. Activated BCR-signaling downstream effectors such as Syk and the Myosin II motor trigger actin cytoskeleton remodeling, promoting an efficient recruitment of MHC class II/Lamp1+molecules toward the Ag−processing compartment. In both schemes, downstream effector molecules control vesicle trafficking and membrane cytoskeleton remodeling, all events dictating lymphocyte effector function.

Mentions: Engagement of the TCR to MHC–peptide complexes after formation of T–APC conjugates results in its down-modulation from the cell surface, a process known to occur in an antigen dose- and time-dependent fashion. TCR down-modulation is controlled at the ISFigure 2 and thought to play a role in T cell desensitization: cSMAC formation enhances TCR signaling for low-affinity Ags, by integrating signaling molecules and co-receptors with engaged TCRs (26). Conversely, stimulation by strong agonists triggers TCR internalization and degradation from the cSMAC, which leads to the down-modulation of TCR signaling (27). TCR internalization is a clathrin-dependent process (28); however, lipid rafts also mediate internalization of TCR signaling components, such as SLP-76 (29). Down-modulation of the TCR from the cell surface can also be achieved by preventing its recycling to the plasma membrane (30) and targeting the receptor for degradation. TCR and corresponding signaling components are targeted for degradation to the lysosomal pathway by means of an ubiquitination signal, an event that was shown to occur in the IS, where ubiquitin is enriched (31). Therefore, by congregating the appropriate molecular effectors, IS formation can promote receptor internalization and degradation, thereby adapting the T cell response to the nature of the stimulus. The down-modulation of the TCR and related signaling components may further contribute to terminate IS formation and function, although the cellular aspects that drive synapse disassembly have not been addressed so far.


Dynamics of membrane trafficking downstream of B and T cell receptor engagement: impact on immune synapses.

Yuseff MI, Lankar D, Lennon-Duménil AM - Traffic (2009)

Later stages of the IS in B and T cells: vesicle trafficking and changes in polarization and membrane morphology determine effector functionsLater stages of lymphocyte activation leads to a dynamic reorganization of the membrane interface characterized by the presence of two concentric regions: cSMAC, where immune-engaged receptors are found and a pSMAC containing adhesion molecules, such as LFA-1 interacting with ligands on the surface of the APC. A) TCR downstream signaling events drive the polarization of the microtubule network, highlighted by the translocation of the MTOC, toward the IS, a mechanism that serves as a guide for the targeted secretion of cytokines. At the IS, engaged TCRs are internalized from the cSMAC, where they can be recycled to the plasma membrane or targeted for degradation by ubiquitination. B) B cells engaged to membrane-bound Ag leads to its extraction, by a yet undefined mechanism. Ag–BCR complexes are transported by ubiquitin signaling into late-endocytic compartments for processing and the derived peptides are loaded onto MHC class II molecules for further presentation to CD4 T cells. Activated BCR-signaling downstream effectors such as Syk and the Myosin II motor trigger actin cytoskeleton remodeling, promoting an efficient recruitment of MHC class II/Lamp1+molecules toward the Ag−processing compartment. In both schemes, downstream effector molecules control vesicle trafficking and membrane cytoskeleton remodeling, all events dictating lymphocyte effector function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2723867&req=5

fig02: Later stages of the IS in B and T cells: vesicle trafficking and changes in polarization and membrane morphology determine effector functionsLater stages of lymphocyte activation leads to a dynamic reorganization of the membrane interface characterized by the presence of two concentric regions: cSMAC, where immune-engaged receptors are found and a pSMAC containing adhesion molecules, such as LFA-1 interacting with ligands on the surface of the APC. A) TCR downstream signaling events drive the polarization of the microtubule network, highlighted by the translocation of the MTOC, toward the IS, a mechanism that serves as a guide for the targeted secretion of cytokines. At the IS, engaged TCRs are internalized from the cSMAC, where they can be recycled to the plasma membrane or targeted for degradation by ubiquitination. B) B cells engaged to membrane-bound Ag leads to its extraction, by a yet undefined mechanism. Ag–BCR complexes are transported by ubiquitin signaling into late-endocytic compartments for processing and the derived peptides are loaded onto MHC class II molecules for further presentation to CD4 T cells. Activated BCR-signaling downstream effectors such as Syk and the Myosin II motor trigger actin cytoskeleton remodeling, promoting an efficient recruitment of MHC class II/Lamp1+molecules toward the Ag−processing compartment. In both schemes, downstream effector molecules control vesicle trafficking and membrane cytoskeleton remodeling, all events dictating lymphocyte effector function.
Mentions: Engagement of the TCR to MHC–peptide complexes after formation of T–APC conjugates results in its down-modulation from the cell surface, a process known to occur in an antigen dose- and time-dependent fashion. TCR down-modulation is controlled at the ISFigure 2 and thought to play a role in T cell desensitization: cSMAC formation enhances TCR signaling for low-affinity Ags, by integrating signaling molecules and co-receptors with engaged TCRs (26). Conversely, stimulation by strong agonists triggers TCR internalization and degradation from the cSMAC, which leads to the down-modulation of TCR signaling (27). TCR internalization is a clathrin-dependent process (28); however, lipid rafts also mediate internalization of TCR signaling components, such as SLP-76 (29). Down-modulation of the TCR from the cell surface can also be achieved by preventing its recycling to the plasma membrane (30) and targeting the receptor for degradation. TCR and corresponding signaling components are targeted for degradation to the lysosomal pathway by means of an ubiquitination signal, an event that was shown to occur in the IS, where ubiquitin is enriched (31). Therefore, by congregating the appropriate molecular effectors, IS formation can promote receptor internalization and degradation, thereby adapting the T cell response to the nature of the stimulus. The down-modulation of the TCR and related signaling components may further contribute to terminate IS formation and function, although the cellular aspects that drive synapse disassembly have not been addressed so far.

Bottom Line: The onset of an adaptive immune response requires the activation of T and B lymphocytes by antigen-presenting cells, through a specialized form of intercellular communication, known as the immunological synapse (IS).In this review, we highlight the similarities that determine B and T cell activation, focusing on immune receptor downstream signaling events that lead to synapse formation.We stress the notion that polarization of T and B lymphocytes characterized by global changes in cytoskeleton and membrane trafficking modulates synapse structure and function, thus determining lymphocyte effector functions and fate.

View Article: PubMed Central - PubMed

Affiliation: INSERM U932, Institut Curie, 75005 Paris, France.

ABSTRACT
The onset of an adaptive immune response requires the activation of T and B lymphocytes by antigen-presenting cells, through a specialized form of intercellular communication, known as the immunological synapse (IS). In B lymphocytes the IS promotes efficient recognition and acquisition of membrane-bound Ags, while in T cells, it modulates the T cell response upon exposure to peptide-major histocompatibility complexes. In this review, we highlight the similarities that determine B and T cell activation, focusing on immune receptor downstream signaling events that lead to synapse formation. We stress the notion that polarization of T and B lymphocytes characterized by global changes in cytoskeleton and membrane trafficking modulates synapse structure and function, thus determining lymphocyte effector functions and fate.

Show MeSH
Related in: MedlinePlus