| 1. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Joshi, Rubin Narayan
(författare)
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T cell signatures and modulation by regulatory T cells
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CD4 T cells are crucial coordinators of protective immune responses against microbes and tumors. However, immune responses misdirected towards self-antigens are the hallmarks of autoimmune diseases. Regulatory T cells (Tregs) maintain peripheral immune tolerance, mainly by suppressing effector T cells. Unfortunately, immunosuppression by Tregs can also favor cancer. Regulating the susceptibility of T cells towards Tregmeditated immunosuppression presents an exciting approach to reconcile between immune activation and tolerance in a disease-specific way. However, less is known about the regulation and mechanism of Treg-mediated suppression in target T cells. The work presented in this thesis is dedicated to unraveling the modulation of signaling cascades in T cells upon T cell receptor (TCR) stimulation and suppression by Tregs. By using unbiased phosphoproteomics, we have mapped the global phosphoproteome of T cells upon TCR stimulation and suppression by Tregs. Our data indicate that Tregs suppress T cells mainly by opposing activation-induced phosphorylation. We discovered that Tregs revert activation-induced phosphorylation of DEF6 at specific sites (T 595 / S 597). Utilizing phospho-mutants, we discovered novel functions of these phosphorylations in disrupting the interaction of DEF6 with the IP3R and regulating T cell signaling via modulation of NFAT activation and transcriptional regulation of T cell cytokines. Upon further exploration of the phosphoproteomic candidate list, we observed similarly altered phospho-regulation of protein phosphatase 1, regulatory subunit 11 (PPP1R11) by Tregs. We revealed that silencing of PPP1R11 renders T cells resistant to Treg-mediation suppression. Our data indicates PPP1R11 to be a novel regulator of T cell activation and Treg-mediated suppression. In light of several reports on resistant T cells in multiple diseases, the phosphoproteomic mapping of suppressed T cells and the insights into novel roles of DEF6 and PPP1R11 from our study may aid in regulating the sensitivity of T cells towards immunosuppression by Tregs in cancer and autoimmune diseases. Besides phosphorylation of proteins, the subcellular localization of proteins is also an important regulatory mechanism of protein activity. Protein localization and activity is modulated by TCR stimulation and was shown for well-known TCR signaling proteins such as NFAT to be affected by Tregs as well. However, these mechanisms are not understood on a global level. Since there is no global data set available on subcellular protein localization and TCR stimulation-induced translocation in primary human T cells, as the first milestone in this field, we have performed a comprehensive mapping of the spatial proteome of T cells and TCR-induced subcellular protein translocation. Besides exploring the target T cell side, in this work we also studied novel methods to induce Tregs, which represents the “other side” of Treg-based immune therapies. We present a novel method of inducing iTregs by using supernatants from M2 macrophages. Our data demonstrate that M2 macrophages induce iTregs by binding and re-releasing TGF-β, which may be explored for Treg induction in situ in the future. Together, by presenting a global picture of T cell protein signaling yet with fine resolution, our work provides new mechanisms and data sets to revisit the role of T cells in therapy, especially in the context of T cell suppression by Tregs.
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| 4. |
- Joshi, Rubin Narayan, et al.
(författare)
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TcellSubC : An Atlas of the Subcellular Proteome of Human T Cells
- 2019
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- We have curated an in-depth subcellular proteomic map of primary human CD4+ T cells, divided into cytosolic, nuclear and membrane fractions generated by an optimized fractionation and HiRIEF-LC-MS/MS workflow for limited amounts of primary cells. The subcellular proteome of T cells was mapped under steady state conditions, as well as upon 15 min and 1 h of T cell receptor (TCR) stimulation, respectively. We quantified the subcellular distribution of 6,572 proteins and identified a subset of 237 potentially translocating proteins, including both well-known examples and novel ones. Microscopic validation confirmed the localization of selected proteins with previously known and unknown localization, respectively. We further provide the data in an easy-to-use web platform to facilitate re-use, as the data can be relevant for basic research as well as for clinical exploitation of T cells as therapeutic targets.
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| 5. |
- Leo, Isabelle Rose, et al.
(författare)
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Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although standard-of-care chemotherapeutics are sufficient for most ALL cases, there are subsets of patients with poor response who relapse in disease. The biology underlying differences between subtypes and their response to therapy has only partially been explained by genetic and transcriptomic profiling. Here, we perform comprehensive multi-omic analyses of 49 readily available childhood ALL cell lines, using proteomics, transcriptomics, and pharmacoproteomic characterization. We connect the molecular phenotypes with drug responses to 528 oncology drugs, identifying drug correlations as well as lineage-dependent correlations. We also identify the diacylglycerol-analog bryostatin-1 as a therapeutic candidate in the MEF2D-HNRNPUL1 fusion high-risk subtype, for which this drug activates pro-apoptotic ERK signaling associated with molecular mediators of pre-B cell negative selection. Our data is the foundation for the interactive online Functional Omics Resource of ALL (FORALL) with navigable proteomics, transcriptomics, and drug sensitivity profiles at https://proteomics.se/fora.
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