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  1. Article ; Online: Factors contributing to the potency of CD8

    Sykulev, Yuri

    Trends in immunology

    2023  Volume 44, Issue 9, Page(s) 693–700

    Abstract: ... ...

    Abstract CD8
    MeSH term(s) Humans ; CD8-Positive T-Lymphocytes ; T-Lymphocytes, Cytotoxic ; Receptors, Antigen, T-Cell/metabolism ; CD8 Antigens ; Killer Cells, Natural
    Chemical Substances Receptors, Antigen, T-Cell ; CD8 Antigens
    Language English
    Publishing date 2023-08-07
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2036831-8
    ISSN 1471-4981 ; 1471-4906
    ISSN (online) 1471-4981
    ISSN 1471-4906
    DOI 10.1016/j.it.2023.07.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: MHC clustering mediates rapid scanning of MHC by CD8 and ensures efficient destruction of target cells by CTL

    Sykulev, Yuri

    Molecular immunology. 2022 Oct., v. 150

    2022  

    Abstract: MHC proteins bearing peptide antigens form nano-scale clusters on the surface of antigen-presenting cells. MHC clustering controls antigen presentation and T-cell responsiveness. Peptide-MHC (pMHC) ligands are recognized by antigen-specific T-cell ... ...

    Abstract MHC proteins bearing peptide antigens form nano-scale clusters on the surface of antigen-presenting cells. MHC clustering controls antigen presentation and T-cell responsiveness. Peptide-MHC (pMHC) ligands are recognized by antigen-specific T-cell receptor (TCR) and binds to CD8 co-receptor. The latter plays a critical role in controlling cytolytic activity of cytotoxic T lymphocytes (CTL). Using nanolipoprotein discoidal membrane mimetics that display pMHC ligands, we have found that close proximity of pMHC ligands within model membrane clusters ensures rapid rebinding of CD8 to MHC accounting for a dual role of CD8, namely, facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid TCR-mediated Ca2+ signaling and target cell destruction of target cells by CTL¹. Our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR occurring at the CTL/target cell interface that regulate antigen recognition, kinetics of intracellular signaling, and efficiency of CTL responses.
    Keywords T-lymphocytes ; antigen presentation ; antigens ; calcium ; cytotoxicity ; ligands ; peptides
    Language English
    Dates of publication 2022-10
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 424427-8
    ISSN 1872-9142 ; 0161-5890
    ISSN (online) 1872-9142
    ISSN 0161-5890
    DOI 10.1016/j.molimm.2022.05.081
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Changing separating distances between immune receptors as a sensitive mechanism regulating T-cell activation.

    Sykulev, Yuri

    Self/nonself

    2011  Volume 1, Issue 1, Page(s) 67–68

    Language English
    Publishing date 2011-01-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2613690-9
    ISSN 1938-2049 ; 1938-2030
    ISSN (online) 1938-2049
    ISSN 1938-2030
    DOI 10.4161/self.1.1.10380
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  4. Article ; Online: The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection.

    Anikeeva, Nadia / Steblyanko, Maria / Kuri-Cervantes, Leticia / Buggert, Marcus / Betts, Michael R / Sykulev, Yuri

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 6436

    Abstract: Chronic HIV infection causes persistent low-grade inflammation that induces premature aging of the immune system including senescence of memory and effector CD8 T cells. To uncover the reasons of gradually diminished potency of CD8 T cells from people ... ...

    Abstract Chronic HIV infection causes persistent low-grade inflammation that induces premature aging of the immune system including senescence of memory and effector CD8 T cells. To uncover the reasons of gradually diminished potency of CD8 T cells from people living with HIV, here we expose the T cells to planar lipid bilayers containing ligands for T-cell receptor and a T-cell integrins and analyze the cellular morphology, dynamics of synaptic interface formation and patterns of the cellular degranulation. We find a large fraction of phenotypically naive T cells from chronically infected people are capable to form mature synapse with focused degranulation, a signature of a differentiated T cells. Further, differentiation of aberrant naive T cells may lead to the development of anomalous effector T cells undermining their capacity to control HIV and other pathogens that could be contained otherwise.
    MeSH term(s) Humans ; HIV Infections ; CD8-Positive T-Lymphocytes ; Lymphocyte Count ; Cell Differentiation ; Synapses
    Language English
    Publishing date 2022-10-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-34157-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: T cell receptor signaling kinetics takes the stage.

    Sykulev, Yuri

    Science signaling

    2010  Volume 3, Issue 153, Page(s) pe50

    Abstract: It has been long surmised that the strength of stimulation of the T cell receptor (TCR) determines the robustness of TCR-mediated signaling and the magnitude of a T cell response. However, it is becoming evident that the signal from the TCR develops over ...

    Abstract It has been long surmised that the strength of stimulation of the T cell receptor (TCR) determines the robustness of TCR-mediated signaling and the magnitude of a T cell response. However, it is becoming evident that the signal from the TCR develops over time to approach its steady-state, affinity-determined maximal extent and that variations in this time have a substantial effect on the responsiveness of T cells. Here, I discuss data that show that the kinetics of signal propagation in various segments of the TCR signaling network can influence the spatiotemporal regulation of the effector functions of T cells and the quality of the T cell response.
    MeSH term(s) Cell Membrane/metabolism ; Humans ; Immunity, Cellular/immunology ; Kinetics ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction/immunology
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2010-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.3153pe50
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection

    Nadia Anikeeva / Maria Steblyanko / Leticia Kuri-Cervantes / Marcus Buggert / Michael R. Betts / Yuri Sykulev

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 12

    Abstract: HIV infection over time is thought to result in premature aging and aberrant immune responses including the induction of immunological senescence. Here the authors show altered formation of immune synapses by naive CD8+ T cells and dysregulated synapse ... ...

    Abstract HIV infection over time is thought to result in premature aging and aberrant immune responses including the induction of immunological senescence. Here the authors show altered formation of immune synapses by naive CD8+ T cells and dysregulated synapse functioning at late differentiated stages in people living with HIV.
    Keywords Science ; Q
    Language English
    Publishing date 2022-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Efficient killing of tumor cells by CAR-T cells requires greater number of engaged CARs than TCRs.

    Anikeeva, Nadia / Panteleev, Sergey / Mazzanti, Nicholas W / Terai, Mizue / Sato, Takami / Sykulev, Yuri

    The Journal of biological chemistry

    2021  Volume 297, Issue 3, Page(s) 101033

    Abstract: Although CAR-T cells are widely used to treat cancer, efficiency of CAR-T cell cytolytic responses has not been carefully examined. We engineered CAR specific for HMW-MAA (high-molecular-weight melanoma-associated antigen) and evaluated potency of CD8+ ... ...

    Abstract Although CAR-T cells are widely used to treat cancer, efficiency of CAR-T cell cytolytic responses has not been carefully examined. We engineered CAR specific for HMW-MAA (high-molecular-weight melanoma-associated antigen) and evaluated potency of CD8+ CAR-T cells to release cytolytic granules and to kill tissue-derived melanoma cells, which express different levels of HMW-MAA. CAR-T cells efficiently killed melanoma cells expressing high level of HMW-MAA, but not melanoma cells with lower levels of HMW-MAA. The same melanoma cells presenting significantly lower level of stimulatory peptide-MHC ligand were readily lysed by T cells transduced with genes encoding α,β-TCR specific for the peptide-MHC ligand. The data suggest that higher level of targeted molecules is required to engage a larger number of CARs than TCRs to induce efficient cytolytic granule release and destruction of melanoma cells. Understanding the difference in molecular mechanisms controlling activation thresholds of CAR- versus TCR-mediated responses will contribute to improving efficiency of CAR T cells required to eliminate solid tumors presenting low levels of targeted molecules.
    MeSH term(s) Antigens, Neoplasm/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Death/immunology ; Cell Line, Tumor ; HLA-A2 Antigen/immunology ; Humans ; Immunotherapy, Adoptive ; Lymphocyte Activation ; Melanoma/immunology ; Melanoma/pathology ; Melanoma/therapy ; Receptors, Antigen, T-Cell/immunology ; Receptors, Chimeric Antigen/immunology
    Chemical Substances Antigens, Neoplasm ; HLA-A2 Antigen ; HMW-MAA ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
    Language English
    Publishing date 2021-08-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2021.101033
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  8. Article ; Online: Herman N. Eisen: Mentor to many.

    Kranz, David M / Sykulev, Yuri

    Proceedings of the National Academy of Sciences of the United States of America

    2015  Volume 112, Issue 6, Page(s) 1650–1651

    MeSH term(s) Allergy and Immunology/history ; Career Choice ; Epitopes ; History, 20th Century ; History, 21st Century
    Chemical Substances Epitopes
    Language English
    Publishing date 2015-02-10
    Publishing country United States
    Document type Biography ; Historical Article ; Journal Article ; Portraits
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1500050112
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  9. Article ; Online: The DISC1-Girdin complex - a missing link in signaling to the T cell cytoskeleton.

    Maskalenko, Nicholas / Nath, Shubhankar / Ramakrishnan, Adarsh / Anikeeva, Nadia / Sykulev, Yuri / Poenie, Martin

    Journal of cell science

    2020  Volume 133, Issue 13

    Abstract: In this study, using Jurkat cells, we show that DISC1 (disrupted in schizophrenia 1) and Girdin (girders of actin filament) are essential for typical actin accumulation at the immunological synapse. Furthermore, DISC1, Girdin and dynein are bound in a ... ...

    Abstract In this study, using Jurkat cells, we show that DISC1 (disrupted in schizophrenia 1) and Girdin (girders of actin filament) are essential for typical actin accumulation at the immunological synapse. Furthermore, DISC1, Girdin and dynein are bound in a complex. Although this complex initially forms as a central patch at the synapse, it relocates to a peripheral ring corresponding to the peripheral supramolecular activation cluster (pSMAC). In the absence of DISC1, the classic actin ring does not form, cell spreading is blocked, and the dynein complex fails to relocate to the pSMAC. A similar effect is seen when Girdin is deleted. When cells are treated with inhibitors of actin polymerization, the dynein-NDE1 complex is lost from the synapse and the microtubule-organizing center fails to translocate, suggesting that actin and dynein might be linked. Upon stimulation of T cell receptors, DISC1 becomes associated with talin, which likely explains why the dynein complex colocalizes with the pSMAC. These results show that the DISC1-Girdin complex regulates actin accumulation, cell spreading and distribution of the dynein complex at the synapse.This article has an associated First Person interview with the first author of the paper.
    MeSH term(s) Actins/metabolism ; Cytoskeleton/metabolism ; Humans ; Immunological Synapses/metabolism ; Microtubule-Associated Proteins ; Microtubules/metabolism ; Nerve Tissue Proteins/genetics ; Signal Transduction
    Chemical Substances Actins ; DISC1 protein, human ; Microtubule-Associated Proteins ; Nde1 protein, human ; Nerve Tissue Proteins
    Language English
    Publishing date 2020-07-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.242875
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses.

    Anikeeva, Nadia / Fischer, Nicholas O / Blanchette, Craig D / Sykulev, Yuri

    Journal of immunology (Baltimore, Md. : 1950)

    2018  Volume 202, Issue 2, Page(s) 591–597

    Abstract: MHC proteins that present peptide ligands for recognition by TCR form nanoscale clusters on the cell membrane of APCs. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To ... ...

    Abstract MHC proteins that present peptide ligands for recognition by TCR form nanoscale clusters on the cell membrane of APCs. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nanoscale discoidal membrane mimetics (nanolipoprotein particles) to capture and present peptide-MHC (pMHC) ligands at various densities. We examined the binding of these model membrane clusters to the surface of live human CD8
    MeSH term(s) Binding Sites ; Biomimetics ; CD8-Positive T-Lymphocytes/immunology ; Histocompatibility Antigens Class I/immunology ; Humans ; Kinetics ; Lymphocyte Activation ; Peptides/chemistry ; Protein Binding ; Receptors, Antigen, T-Cell/immunology ; Signal Transduction
    Chemical Substances Histocompatibility Antigens Class I ; Peptides ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2018-12-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1801196
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