Publications by authors named "Sibel Durlanik"

7 Publications

  • Page 1 of 1

CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1.

Sci Rep 2021 Jul 21;11(1):14849. Epub 2021 Jul 21.

Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach, Germany.

More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7-H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.
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http://dx.doi.org/10.1038/s41598-021-94360-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295264PMC
July 2021

SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8 T cells.

Nat Commun 2020 12 11;11(1):6357. Epub 2020 Dec 11.

Si-M/"Der Simulierte Mensch" a science framework of Technische Universität Berlin and Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.

The prevailing 'division of labor' concept in cellular immunity is that CD8 T cells primarily utilize cytotoxic functions to kill target cells, while CD4 T cells exert helper/inducer functions. Multiple subsets of CD4 memory T cells have been characterized by distinct chemokine receptor expression. Here, we demonstrate that analogous CD8 memory T-cell subsets exist, characterized by identical chemokine receptor expression signatures and controlled by similar generic programs. Among them, Tc2, Tc17 and Tc22 cells, in contrast to Tc1 and Tc17 + 1 cells, express IL-6R but not SLAMF7, completely lack cytotoxicity and instead display helper functions including CD40L expression. CD8 helper T cells exhibit a unique TCR repertoire, express genes related to skin resident memory T cells (T) and are altered in the inflammatory skin disease psoriasis. Our findings reveal that the conventional view of CD4 and CD8 T cell capabilities and functions in human health and disease needs to be revised.
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http://dx.doi.org/10.1038/s41467-020-19002-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733515PMC
December 2020

CD40L expression by CD4 but not CD8 T cells regulates antiviral immune responses in acute LCMV infection in mice.

Eur J Immunol 2016 11 20;46(11):2566-2573. Epub 2016 Sep 20.

Regenerative Immunology and Aging, Berlin-Brandenburger Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.

CD40-CD40 ligand (CD40L) signaling plays multiple indispensable roles in cellular and humoral immunity. Impaired memory T-cell responses in the absence of CD40L have been well documented, but the requirement of this interaction for efficient priming of CD8 T cells especially under inflammatory conditions has been under debate. In contrast to previous publications, we report here that virus-specific CD8 T-cell responses as well as viral clearance are affected not only in the memory but also in the effector phase in CD40L mice infected with lymphocytic choriomeningitis virus (LCMV) Armstrong strain. Interestingly, a considerable part of the LCMV-specific effector and memory T cells consists of CD40L CD8 T cells. However, deficiency of CD40L in CD8 T cells did influence neither the quantity nor the quality of primary T-cell responses in LCMV infection. Virus-specific CD8 T cells in conditional knockout mice, with a selective deletion of the CD40L in CD8 T cells, were fully functional regarding cytokine production and efficient pathogen clearance. Thus, our results unambiguously demonstrate that while CD40L is critical to generate effective primary CD8 T-cell responses also under inflammatory conditions, CD40L expression by CD8 T cells themselves is dispensable in acute LCMV infection.
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http://dx.doi.org/10.1002/eji.201646420DOI Listing
November 2016

Requirement of immune system heterogeneity for protective immunity.

Vaccine 2015 Sep 11;33(40):5308-12. Epub 2015 Jun 11.

Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, CVK, Föhrer Str. 15, Berlin 13353, Germany.

Although our knowledge on the immune system and immunological memory has expanded enormously during the last decades, the development of strategies to induce robust protective memory against infections and tumors remains challenging. Intense efforts and immense resources have been put into the development of vaccines. However, effective tools to assess protective immunity, beyond neutralizing antibody titers and cytotoxic T cell activity, are still missing. Previous trials have primarily focused on individual cell subsets to induce and maintain protection while current research emphasizes the importance of functional heterogeneity and necessity of efficient communication within the immunological network. In this review, established knowledge as well as current perspectives on protective immunological memory will be discussed comprehensively.
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http://dx.doi.org/10.1016/j.vaccine.2015.05.096DOI Listing
September 2015

Memory CD8(+) T cells colocalize with IL-7(+) stromal cells in bone marrow and rest in terms of proliferation and transcription.

Eur J Immunol 2015 Apr 27;45(4):975-87. Epub 2015 Feb 27.

Department of Cell Biology, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.

It is believed that memory CD8(+) T cells are maintained in secondary lymphoid tissues, peripheral tissues, and BM by homeostatic proliferation. Their survival has been shown to be dependent on IL-7, but it is unclear where they acquire it. Here we show that in murine BM, memory CD8(+) T cells individually colocalize with IL-7(+) reticular stromal cells. The T cells are resting in terms of global transcription and do not express markers of activation, for example, 4-1BB (CD137), IL-2, or IFN-γ, despite the expression of CD69 on about 30% of the cells. Ninety-five percent of the memory CD8(+) T cells in BM are in G0 phase of cell cycle and do not express Ki-67. Less than 1% is in S/M/G2 of cell cycle, according to propidium iodide staining. While previous publications have estimated the extent of proliferation of CD8(+) memory T cells on the basis of BrdU incorporation, we show here that BrdU itself induces proliferation of CD8(+) memory T cells. Taken together, the present results suggest that CD8(+) memory T cells are maintained as resting cells in the BM in dedicated niches with their survival conditional on IL-7 receptor signaling.
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http://dx.doi.org/10.1002/eji.201445295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415462PMC
April 2015

CD40L expression permits CD8+ T cells to execute immunologic helper functions.

Blood 2013 Jul 29;122(3):405-12. Epub 2013 May 29.

Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany.

CD8(+) T cells play an essential role in immunity against intracellular pathogens, with cytotoxicity being considered their major effector mechanism. However, we here demonstrate that a major part of central and effector memory CD8(+) T cells expresses CD40L, one key molecule for CD4(+) T-cell-mediated help. CD40L(+) CD8(+) T cells are detectable among human antigen-specific immune responses, including pathogens such as influenza and yellow fever virus. CD40L(+) CD8(+) T cells display potent helper functions in vitro and in vivo, such as activation of antigen-presenting cells, and exhibit a cytokine expression signature similar to CD4(+) T cells and unrelated to cytotoxic CD8(+) T cells. The broad occurrence of CD40L(+) CD8(+) T cells in cellular immunity implicates that helper functions are not only executed by major histocompatibility complex (MHC) class II-restricted CD4(+) helper T cells but are also a common feature of MHC class I-restricted CD8(+) T cell responses. Due to their versatile functional capacities, human CD40L(+) CD8(+) T cells are promising candidate cells for immune therapies, particularly when CD4(+) T-cell help or pathogen-associated molecular pattern signals are limited.
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http://dx.doi.org/10.1182/blood-2013-02-483586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548794PMC
July 2013

Pathogen-triggered activation of plasmacytoid dendritic cells induces IL-10-producing B cells in response to Staphylococcus aureus.

J Immunol 2013 Feb 16;190(4):1591-602. Epub 2013 Jan 16.

Department of Infectious Diseases, Medical Microbiology, and Hygiene, University Hospital Heidelberg, D-69120 Heidelberg, Germany.

Induction of polyclonal B cell activation is a phenomenon observed in many types of infection, but its immunological relevance is unclear. In this study we show that staphylococcal protein A induces T cell-independent human B cell proliferation by enabling uptake of TLR-stimulating nucleic acids via the V(H)3(+) BCR. We further demonstrate that Staphylococcus aureus strains with high surface protein A expression concomitantly trigger activation of human plasmacytoid dendritic cells (pDC). Sensitivity to chloroquine, cathepsin B inhibition, and a G-rich inhibitory oligodeoxynucleotide supports the involvement of TLR9 in this context. We then identify pDC as essential cellular mediators of B cell proliferation and Ig production in response to surface protein A-bearing S. aureus. The in vivo relevancy of these findings is confirmed in a human PBMC Nod/scid(Prkdc)/γc(-/-) mouse model. Finally, we demonstrate that co-operation of pDC and B cells enhances B cell-derived IL-10 production, a cytokine associated with immunosuppression and induction of IgG4, an isotype frequently dominating the IgG response to S. aureus. IL-10 release is partially dependent on TLR2-active lipoproteins, a hallmark of the Staphylococcus species. Collectively, our data suggest that S. aureus exploits pDC and TLR to establish B cell-mediated immune tolerance.
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http://dx.doi.org/10.4049/jimmunol.1201222DOI Listing
February 2013
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