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Article ; Online: Lymphocyte Polarization During Immune Synapse Assembly: Centrosomal Actin Joins the Game.

Cassioli, Chiara / Baldari, Cosima T

2022 Volume 13, Page(s) 830835

Abstract: Interactions among immune cells are essential for the development of adaptive immune responses. The immunological synapse (IS) provides a specialized platform for integration of signals and intercellular communication between T lymphocytes and antigen ... ...

Abstract	Interactions among immune cells are essential for the development of adaptive immune responses. The immunological synapse (IS) provides a specialized platform for integration of signals and intercellular communication between T lymphocytes and antigen presenting cells (APCs). In the T cell the reorganization of surface molecules at the synaptic interface is initiated by T cell receptor binding to a cognate peptide-major histocompatibility complex on the APC surface and is accompanied by a polarized remodelling of the cytoskeleton and centrosome reorientation to a subsynaptic position. Although there is a general agreement on polarizing signals and mechanisms driving centrosome reorientation during IS assembly, the primary events that prepare for centrosome repositioning remain largely unexplored. It has been recently shown that in resting lymphocytes a local polymerization of filamentous actin (F-actin) at the centrosome contributes to anchoring this organelle to the nucleus. During early stages of IS formation centrosomal F-actin undergoes depletion, allowing for centrosome detachment from the nucleus and its polarization towards the synaptic membrane. We recently demonstrated that in CD4
MeSH term(s)	Actins/metabolism ; Lymphocyte Activation ; Lymphocytes ; Proteasome Endopeptidase Complex ; Synapses
Chemical Substances	Actins ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2022-02-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.830835
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The Expanding Arsenal of Cytotoxic T Cells.

Cassioli, Chiara / Baldari, Cosima T

Frontiers in immunology

2022 Volume 13, Page(s) 883010

Abstract: Cytotoxic T cells (CTLs) are the main cellular mediators of the adaptive immune defenses against intracellular pathogens and malignant cells. Upon recognition of specific antigen on their cellular target, CTLs assemble an immunological synapse where they ...

Abstract	Cytotoxic T cells (CTLs) are the main cellular mediators of the adaptive immune defenses against intracellular pathogens and malignant cells. Upon recognition of specific antigen on their cellular target, CTLs assemble an immunological synapse where they mobilise their killing machinery that is released into the synaptic cleft to orchestrate the demise of their cell target. The arsenal of CTLs is stored in lysosome-like organelles that undergo exocytosis in response to signals triggered by the T cell antigen receptor following antigen recognition. These organelles include lytic granules carrying a cargo of cytotoxic proteins packed on a proteoglycan scaffold, multivesicular bodies carrying the death receptor ligand FasL, and the recently discovered supramolecular attack particles that carry a core of cytotoxic proteins encased in a non-membranous glycoprotein shell. Here we will briefly review the main features of these killing entities and discuss their interrelationship and interplay in CTL-mediated killing.
MeSH term(s)	Cytoplasmic Granules ; Exocytosis ; Immunological Synapses/metabolism ; Perforin/metabolism ; T-Lymphocytes, Cytotoxic
Chemical Substances	Perforin (126465-35-8)
Language	English
Publishing date	2022-04-20
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.883010
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Article ; Online: Exploiting the RUSH System to Study Lytic Granule Biogenesis in Cytotoxic T Lymphocytes.

Capitani, Nagaja / Cassioli, Chiara / Ravichandran, Keerthana / Baldari, Cosima T

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2654, Page(s) 421–436

Abstract: The Retention Using Selective Hooks (RUSH) system allows for the synchronized release of one or more proteins of interest from a donor endomembrane compartment, usually the endoplasmic reticulum, and the subsequent monitoring of their traffic toward ... ...

Abstract	The Retention Using Selective Hooks (RUSH) system allows for the synchronized release of one or more proteins of interest from a donor endomembrane compartment, usually the endoplasmic reticulum, and the subsequent monitoring of their traffic toward acceptor compartments. Here we describe the RUSH system applied to cytotoxic T cells to characterize the biogenesis of lytic granules, using as a proof-of-concept granzyme B trafficking to this specialized compartment.
MeSH term(s)	T-Lymphocytes, Cytotoxic/metabolism ; Proteins/metabolism ; Cytoplasmic Granules/metabolism
Chemical Substances	Proteins
Language	English
Publishing date	2023-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3135-5_27
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Article ; Online: A Ciliary View of the Immunological Synapse.

Cassioli, Chiara / Baldari, Cosima T

Cells

2019 Volume 8, Issue 8

Abstract: The primary cilium has gone from being a vestigial organelle to a crucial signaling hub of growing interest given the association between a group of human disorders, collectively known as ciliopathies, and defects in its structure or function. In recent ... ...

Abstract	The primary cilium has gone from being a vestigial organelle to a crucial signaling hub of growing interest given the association between a group of human disorders, collectively known as ciliopathies, and defects in its structure or function. In recent years many ciliogenesis proteins have been observed at extraciliary sites in cells and likely perform cilium-independent functions ranging from regulation of the cytoskeleton to vesicular trafficking. Perhaps the most striking example is the non-ciliated T lymphocyte, in which components of the ciliary machinery are repurposed for the assembly and function of the immunological synapse even in the absence of a primary cilium. Furthermore, the specialization traits described at the immunological synapse are similar to those seen in the primary cilium. Here, we review common regulators and features shared by the immunological synapse and the primary cilium that document the remarkable homology between these structures.
MeSH term(s)	Cilia/metabolism ; Ciliopathies/metabolism ; Cytoskeleton/metabolism ; Humans ; Immunological Synapses/metabolism ; T-Lymphocytes/metabolism
Language	English
Publishing date	2019-07-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8080789
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Article ; Online: Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs).

Cassioli, Chiara / Patrussi, Laura / Valitutti, Salvatore / Baldari, Cosima T

International journal of molecular sciences

2022 Volume 23, Issue 22

Abstract: Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic ...

Abstract	Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response.
MeSH term(s)	Humans ; Receptors, Chimeric Antigen ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Immunological Synapses/metabolism ; T-Lymphocytes ; Lymphocyte Activation
Chemical Substances	Receptors, Chimeric Antigen
Language	English
Publishing date	2022-11-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232214255
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Article ; Online: Human colorectal cancer: upregulation of the adaptor protein Rai in TILs leads to cell dysfunction by sustaining GSK-3 activation and PD-1 expression.

Montecchi, Tommaso / Nannini, Giulia / De Tommaso, Domiziana / Cassioli, Chiara / Coppola, Federica / Ringressi, Maria Novella / Carraro, Fabio / Naldini, Antonella / Taddei, Antonio / Marotta, Giuseppe / Amedei, Amedeo / Baldari, Cosima T / Ulivieri, Cristina

Cancer immunology, immunotherapy : CII

2024 Volume 73, Issue 1, Page(s) 2

Abstract: Background: The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a ... ...

Abstract	Background: The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a critical need for the discovery of novel therapeutic targets and the development of effective therapies. We previously showed that (i) the adaptor protein Rai is a negative regulator of T cell receptor signaling and T helper 1 (Th1)/Th17 cell differentiation; and (ii) Rai deficiency is implicated in the hyperactive phenotype of T cells in autoimmune diseases. Methods: The expression level of Rai was measured by qRT-PCR in paired peripheral blood T cells and T cells infiltrating tumor tissue and the normal adjacent tissue in CRC patients. The impact of hypoxia-inducible factor (HIF)-1α on Rai expression was evaluated in T cells exposed to hypoxia and by performing chromatin immunoprecipitation assays and RNA interference assays. The mechanism by which upregulation of Rai in T cells promotes T cell exhaustion were evaluated by flow cytometric, qRT-PCR and western blot analyses. Results: We show that Rai is a novel HIF-1α-responsive gene that is upregulated in tumor infiltrating lymphocytes of CRC patients compared to patient-matched circulating T cells. Rai upregulation in T cells promoted Programmed cell Death protein (PD)-1 expression and impaired antigen-dependent degranulation of CD8 Conclusions: Our data identify Rai as a hitherto unknown regulator of the TME-induced exhausted phenotype of human T cells.
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes ; Colorectal Neoplasms/genetics ; Glycogen Synthase Kinase 3 ; Hypoxia ; Lymphocytes, Tumor-Infiltrating ; Programmed Cell Death 1 Receptor/genetics ; Tumor Microenvironment ; Up-Regulation
Chemical Substances	Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Programmed Cell Death 1 Receptor ; PDCD1 protein, human ; PPP1R13L protein, human
Language	English
Publishing date	2024-01-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-023-03614-0
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Article: Regulation of Selective B Cell Autophagy by the Pro-oxidant Adaptor p66SHC.

Onnis, Anna / Cassioli, Chiara / Finetti, Francesca / Baldari, Cosima T

Frontiers in cell and developmental biology

2020 Volume 8, Page(s) 193

Abstract: p66SHC is a pro-oxidant member of the SHC family of protein adaptors that acts as a negative regulator of cell survival. In lymphocytes p66SHC exploits both its adaptor and its reactive oxygen species (ROS)-elevating function to antagonize mitogenic and ... ...

Abstract	p66SHC is a pro-oxidant member of the SHC family of protein adaptors that acts as a negative regulator of cell survival. In lymphocytes p66SHC exploits both its adaptor and its reactive oxygen species (ROS)-elevating function to antagonize mitogenic and survival signaling and promote apoptosis. As a result, p66SHC deficiency leads to the abnormal expansion of peripheral T and B cells and lupus-like autoimmunity. Additionally, a defect in p66SHC expression is a hallmark of B cell chronic lymphocytic leukemia, where it contributes to the accumulation of long-lived neoplastic cells. We have recently provided evidence that p66SHC exerts a further layer of control on B cell homeostasis by acting as a new mitochondrial LC3-II receptor to promote the autophagic demise of dysfunctional mitochondria. Here we discuss this finding in the context of the autophagic control of B cell homeostasis, development, and differentiation in health and disease.
Language	English
Publishing date	2020-03-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2020.00193
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Article: Transcellular communication at the immunological synapse: a vesicular traffic-mediated mutual exchange.

Finetti, Francesca / Cassioli, Chiara / Baldari, Cosima T

F1000Research

2017 Volume 6, Page(s) 1880

Abstract: The cell's ability to communicate with the extracellular environment, with other cells, and with itself is a crucial feature of eukaryotic organisms. In the immune system, T lymphocytes assemble a specialized structure upon contact with antigen- ... ...

Abstract	The cell's ability to communicate with the extracellular environment, with other cells, and with itself is a crucial feature of eukaryotic organisms. In the immune system, T lymphocytes assemble a specialized structure upon contact with antigen-presenting cells bearing a peptide-major histocompatibility complex ligand, known as the immunological synapse (IS). The IS has been extensively characterized as a signaling platform essential for T-cell activation. Moreover, emerging evidence identifies the IS as a device for vesicular traffic-mediated cell-to-cell communication as well as an active release site of soluble molecules. Here, we will review recent advances in the role of vesicular trafficking in IS assembly and focused secretion of microvesicles at the synaptic area in naïve T cells and discuss the role of the IS in transcellular communication.
Language	English
Publishing date	2017
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2699932-8
ISSN	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.11944.1
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Article: The Intraflagellar Transport Protein IFT20 Recruits ATG16L1 to Early Endosomes to Promote Autophagosome Formation in T Cells.

Finetti, Francesca / Cassioli, Chiara / Cianfanelli, Valentina / Zevolini, Fabrizia / Onnis, Anna / Gesualdo, Monica / Brunetti, Jlenia / Cecconi, Francesco / Baldari, Cosima T

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 634003

Abstract: Lymphocyte homeostasis, activation and differentiation crucially rely on basal autophagy. The fine-tuning of this process depends on autophagy-related (ATG) proteins and their interaction with the trafficking machinery that orchestrates the membrane ... ...

Abstract	Lymphocyte homeostasis, activation and differentiation crucially rely on basal autophagy. The fine-tuning of this process depends on autophagy-related (ATG) proteins and their interaction with the trafficking machinery that orchestrates the membrane rearrangements leading to autophagosome biogenesis. The underlying mechanisms are as yet not fully understood. The intraflagellar transport (IFT) system, known for its role in cargo transport along the axonemal microtubules of the primary cilium, has emerged as a regulator of autophagy in ciliated cells. Growing evidence indicates that ciliogenesis proteins participate in cilia-independent processes, including autophagy, in the non-ciliated T cell. Here we investigate the mechanism by which IFT20, an integral component of the IFT system, regulates basal T cell autophagy. We show that IFT20 interacts with the core autophagy protein ATG16L1 and that its CC domain is essential for its pro-autophagic activity. We demonstrate that IFT20 is required for the association of ATG16L1 with the Golgi complex and early endosomes, both of which have been identified as membrane sources for phagophore elongation. This involves the ability of IFT20 to interact with proteins that are resident at these subcellular localizations, namely the golgin GMAP210 at the Golgi apparatus and Rab5 at early endosomes. GMAP210 depletion, while leading to a dispersion of ATG16L1 from the Golgi, did not affect basal autophagy. Conversely, IFT20 was found to recruit ATG16L1 to early endosomes tagged for autophagosome formation by the BECLIN 1/VPS34/Rab5 complex, which resulted in the local accumulation of LC3. Hence IFT20 participates in autophagosome biogenesis under basal conditions by regulating the localization of ATG16L1 at early endosomes to promote autophagosome biogenesis. These data identify IFT20 as a new regulator of an early step of basal autophagy in T cells.
Language	English
Publishing date	2021-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.634003
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Article ; Online: SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly.

Onnis, Anna / Andreano, Emanuele / Cassioli, Chiara / Finetti, Francesca / Della Bella, Chiara / Staufer, Oskar / Pantano, Elisa / Abbiento, Valentina / Marotta, Giuseppe / D'Elios, Mario Milco / Rappuoli, Rino / Baldari, Cosima T

The Journal of experimental medicine

2022 Volume 220, Issue 2

Abstract: CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, ...

Abstract	CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). IS defects were also observed ex vivo in CTLs from COVID-19 patients. These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells.
MeSH term(s)	Humans ; Spike Glycoprotein, Coronavirus ; Angiotensin-Converting Enzyme 2 ; SARS-CoV-2 ; COVID-19 ; Peptidyl-Dipeptidase A/metabolism ; Synapses/metabolism ; Protein Binding
Chemical Substances	spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2022-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20220906
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