Federica Sallusto

Last Name

Sallusto

First Name

Federica

ORCID

0000-0003-3750-2752

Organisational unit

09604 - Sallusto, Federica / Sallusto, Federica

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Publications 1 - 10 of 76

Broadly reactive human CD4 + T cells against Enterobacteriaceae are found in the naïve repertoire and are clonally expanded in the memory repertoire
Cassotta, Antonino; Goldstein, Jérémie D.; Durini, Greta; et al. (2021)
European Journal of Immunology
Enterobacteriaceae are a large family of Gram-negative bacteria that includes both commensals and opportunistic pathogens. The latter can cause severe nosocomial infections, with outbreaks. This T cell subset was severely reduced in septic patients with K. pneumoniae bloodstream infection who also selectively lacked circulating K. pneumoniereactive to several Enterobacteriaceae species. These cross-reactive Th cell clones were expanded in vivo and a large fraction of them recognized the conserved outer membrane protein A (OmpA) antigen. Interestingly, Enterobacteriaceae broadly reactive T cells were also prominent among in vitro primed T cells. Collectively, these data point to the existence of immunodominant T cell epitopes shared among different Enterobacteriaceae species and targeted byT cells that are readily found in the pre-immune repertoire and are clonally expanded in the memory repertoire.
Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes
Kallewaard, Nicole L.; Corti, Davide; Collins, Patrick J.; et al. (2016)
Cell
Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross-reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans.
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
Geiger, Roger; Rieckmann, Jan C.; Wolf, Tobias; et al. (2016)
Cell
Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses.
CXCR3 Identifies Human Naive CD8⁺ T Cells with Enhanced Effector Differentiation Potential
De Simone, Gabriele; Mazza, Emilia M.C.; Cassotta, Antonino; et al. (2019)
The Journal of Immunology
n mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide–HLA class I Ags. Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells.
Narcolepsy: a model interaction between immune system, nervous system, and sleep-wake regulation
Latorre, Daniela; Sallusto, Federica; Bassetti, Claudio L.A.; et al. (2022)
Seminars in Immunopathology
Narcolepsy is a rare chronic neurological disorder characterized by an irresistible excessive daytime sleepiness and cataplexy. The disease is considered to be the result of the selective disruption of neuronal cells in the lateral hypothalamus expressing the neuropeptide hypocretin, which controls the sleep-wake cycle. Diagnosis and management of narcolepsy represent still a substantial medical challenge due to the large heterogeneity in the clinical manifestation of the disease as well as to the lack of understanding of the underlying pathophysiological mechanisms. However, significant advances have been made in the last years, thus opening new perspective in the field. This review describes the current knowledge of clinical presentation and pathology of narcolepsy as well as the existing diagnostic criteria and therapeutic intervention for the disease management. Recent evidence on the potential immune-mediated mechanisms that may underpin the disease establishment and progression are also highlighted.
Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner
Farsakoglu, Yagmur; Palomino-Segura, Miguel; Latino, Irene; et al. (2019)
Cell Reports
The role of natural killer (NK) cells in the immune response against vaccines is not fully understood. Here, we examine the function of infiltrated NK cells in the initiation of the inflammatory response triggered by inactivated influenza virus vaccine in the draining lymph node (LN). We observed that, following vaccination, NK cells are recruited to the interfollicular and medullary areas of the LN and become activated by type I interferons (IFNs) produced by LN macrophages. The activation of NK cells leads to their early production of IFNγ, which in turn regulates the recruitment of IL-6+ CD11b+ dendritic cells. Finally, we demonstrate that the interleukin-6 (IL-6)-mediated inflammation is important for the development of an effective humoral response against influenza virus in the draining LN.
Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2
Low, Jun Siong; Vaqueirinho, Daniela; Mele, Federico; et al. (2021)
Science
The identification of CD4$^+$ T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here, we demonstrate in COVID-19–recovered individuals a robust CD4$^+$ T cell response to naturally processed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that the receptor-binding domain (RBD) is highly immunogenic and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346–S365 region comprising nested human leukocyte antigen DR (HLA-DR)– and HLA-DP–restricted epitopes. Using pre– and post–COVID-19 samples and S proteins from endemic coronaviruses, we identified cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.
Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus
Marcandalli, Jessica; Fiala, Brooke; Ols, Sebastian; et al. (2019)
Cell
Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.
Antibodies Produced by CLL Phenotype B Cells in Patients With Myasthenia Gravis Are Not Directed Against Neuromuscular Endplates
Ingelfinger, Florian; Kramer, Michael; Lutz, Mirjam; et al. (2023)
Neurology: Neuroimmunology & Neuroinflammation
Background and Objectives Myasthenia gravis (MG) can in rare cases be an autoimmune phenomenon associated with hematologic malignancies such as chronic lymphocytic leukemia (CLL). It is unclear whether in patients with MG and CLL, the leukemic B cells are the ones directly driving the autoimmune response against neuromuscular endplates. Methods We identified patients with acetylcholine receptor antibody–positive (AChR+) MG and CLL or monoclonal B-cell lymphocytosis (MBL), a precursor to CLL, and described their clinical features, including treatment responses. We generated recombinant monoclonal antibodies (mAbs) corresponding to the B-cell receptors of the CLL phenotype B cells and screened them for autoantigen binding. Results A computational immune cell screen revealed a subgroup of 5/38 patients with MG and 0/21 healthy controls who displayed a CLL-like B-cell phenotype. In follow-up hematologic flow cytometry, 2 of these 5 patients were diagnosed with an MBL. An additional patient with AChR+ MG as a complication of manifest CLL presented at our neuromuscular clinic and was successfully treated with the anti-CD20 therapy obinutuzumab plus chlorambucil. We investigated the specificities of expanding CLL-like B-cell clones to assess a direct causal link between the 2 diseases. However, we observed no reactivity of the clones against the AChR, antigens at the neuromuscular junction, or other common autoantigens. Discussion Our study suggests that AChR autoantibodies are produced by nonmalignant, polyclonal B cells The new anti-CD20 treatment obinutuzumab might be considered in effectively treating AChR+ MG. Classification of Evidence This is a single case study and provides Class IV evidence that obinutuzumab is safe to use in patients with MG.
Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients
Rodríguez-Frade, José Miguel; Gardeta, Sofía R.; D'Agostino, Gianluca; et al. (2022)
Proceedings of the National Academy of Sciences of the United States of America
SignificanceNew imaging-based approaches are incorporating new concepts to our knowledge of biological processes. The analysis of receptor dynamics involved in cell movement using single-particle tracking demonstrates that cells require chemokine-mediated receptor clustering to sense appropriately chemoattractant gradients. Here, we report that this process does not occur in T cells expressing CXCR4R334X, a mutant form of CXCR4 linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis). The underlaying molecular mechanism involves inappropriate actin cytoskeleton remodeling due to the inadequate β-arrestin1 activation by CXCR4R334X, which alters its lateral mobility and spatial organization. These defects, associated to CXCR4R334X expression, contribute to the retention of hematopoietic precursors in bone marrow niches and explain the severe immunological symptoms associated with WHIM syndrome.

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Federica Sallusto

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