Federica Sallusto
University of Lugano
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Featured researches published by Federica Sallusto.
Nature | 1999
Federica Sallusto; Danielle Lenig; Reinhold Förster; Martin Lipp; Antonio Lanzavecchia
Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.
Nature Immunology | 2007
Eva V. Acosta-Rodríguez; Giorgio Napolitani; Antonio Lanzavecchia; Federica Sallusto
Interleukin 17 (IL-17)–producing CD4+ helper T cells (TH-17 cells) have been linked to host defense and autoimmune diseases. In mice, the differentiation of TH-17 cells requires transforming growth factor-β and IL-6 and the transcription factor RORγt. We report here that for human naive CD4+ T cells, RORγt expression and TH-17 polarization were induced by IL-1β and enhanced by IL-6 but were suppressed by transforming growth factor-β and IL-12. Monocytes and conventional dendritic cells, but not monocyte-derived dendritic cells activated by microbial stimuli, efficiently induced TH-17 priming, and this function correlated with antigen-presenting cell production of IL-1β and IL-6 but not IL-12. Our results identify cytokines, antigen-presenting cells and microbial products that promote the polarization of human TH-17 cells and emphasize an important difference in the requirements for the differentiation of TH-17 cells in humans and mice.
Nature Immunology | 2007
Eva V. Acosta-Rodríguez; Laura Rivino; Jens Geginat; David Jarrossay; Marco Gattorno; Antonio Lanzavecchia; Federica Sallusto; Giorgio Napolitani
Interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) have been characterized in mice as a distinct subset of effector cells, but their identity and properties in humans remain elusive. We report here that expression of CCR6 and CCR4 together identified human memory CD4+ T cells selectively producing IL-17 and expressing mRNA encoding the human ortholog of mouse RORγt, a transcription factor, whereas CCR6 and CXCR3 identified TH1 cells producing interferon-γ and T helper cells producing both interferon-γ and IL-17. Memory T cells specific for Candida albicans were present mainly in the CCR6+CCR4+ TH-17 subset, whereas memory T cells specific for Mycobacterium tuberculosis were present in CCR6+CXCR3+ T helper type 1 subset. The elicitation of IL-17 responses correlated with the capacity of C. albicans hyphae to stimulate antigen-presenting cells for the priming of TH-17 responses in vitro and for the production of IL-23 but not IL-12. Our results demonstrate that human TH-17 cells have distinct migratory capacity and antigenic specificities and establish a link between microbial products, T helper cell differentiation and homing in response to fungal antigens.
Current Opinion in Immunology | 1997
Marina Cella; Federica Sallusto; Antonio Lanzavecchia
Dendritic cells are cells specialized for antigen capture, migration and T cell stimulation. Recent advances have been made in understanding their origin, their heterogeneity, the mechanism of antigen uptake, and the signals that induce their migration and maturation into immunostimulatory antigen-presenting cells. Dendritic cells represent the natural adjuvants for T cell responses and their therapeutic exploitation in the near future is foreseen.
Nature Immunology | 2000
Anja Langenkamp; Mara Messi; Antonio Lanzavecchia; Federica Sallusto
To prime immune responses, dendritic cells (DCs) need to be activated to acquire T cell stimulatory capacity. Although some stimuli trigger interleukin 12 (IL-12) production that leads to T helper cell type 1 (TH1) polarization, others fail to do so and favor TH2 polarization. We show that after activation by lipopolysaccharide, DCs produced IL-12 only transiently and became refractory to further stimulation. The exhaustion of cytokine production impacted the T cell polarizing process. Soon after stimulation DCs primed strong TH1 responses, whereas at later time points the same cells preferentially primed TH2 and nonpolarized T cells. These findings indicate that during an immune response, T cell priming conditions may change in the lymph nodes, suggesting another mechanism for the regulation of effector and memory T cells.
European Journal of Immunology | 1998
Federica Sallusto; Patrick Schaerli; Pius Loetscher; Christoph Schaniel; Danielle Lenig; Charles R. Mackay; Shixin Qin; Antonio Lanzavecchia
Dendritic cells (DC) migrate into inflamed peripheral tissues where they capture antigens and, following maturation, to lymph nodes where they stimulate T cells. To gain insight into this process we compared chemokine receptor expression in immature and mature DC. Immature DC expressed CCR1, CCR2, CCR5 and CXCR1 and responded to their respective ligands, which are chemokines produced at inflammatory sites. Following stimulation with LPS or TNF‐α maturing DC expressed high levels of CCR7 mRNA and acquired responsiveness to the CCR7 ligand EBI1 ligand chemokine (ELC), a chemokine produced in lymphoid organs. Maturation also resulted in up‐regulation of CXCR4 and down‐regulation of CXCR1 mRNA, while CCR1 and CCR5 mRNA were only marginally affected for up to 40 h. However, CCR1 and CCR5 were lost from the cell surface within 3 h, due to receptor down‐regulation mediated by chemokines produced by maturing DC. A complete down‐regulation of CCR1 and CCR5 mRNA was observed only after stimulation with CD40 ligand of DC induced to mature by LPS treatment. These different patterns of chemokine receptors are consistent with “inflammatory” and “primary response” phases of DC function.
Nature Immunology | 2004
Alfonso Martín-Fontecha; Lindy L. Thomsen; Sara Brett; Craig Gerard; Martin Lipp; Antonio Lanzavecchia; Federica Sallusto
Naive T cells are stimulated by antigen-presenting dendritic cells (DCs) in secondary lymphoid organs, but whether other types of cell participate in T cell priming is unclear. Here we show in mice that natural killer (NK) cells, which are normally excluded from lymph nodes, are rapidly recruited in a CCR7-independent, CXCR3-dependent manner to lymph nodes on stimulation by the injection of mature DCs. Recruitment of NK cells is also induced by some, but not all, adjuvants and correlates with the induction of T helper cell type 1 (TH1) responses. NK cell depletion and reconstitution experiments show that NK cells provide an early source of interferon-γ (IFN-γ) that is necessary for TH1 polarization. Taken together, our results identify an induced pathway of NK cell migration in antigen-stimulated lymph nodes and a mechanism by which some adjuvants may facilitate TH1 responses.
PLOS Medicine | 2009
Surender Khurana; Amorsolo L. Suguitan; Yonaira Rivera; Cameron P. Simmons; Antonio Lanzavecchia; Federica Sallusto; Jody Manischewitz; Lisa R. King; Kanta Subbarao; Hana Golding
Using whole-genome-fragment phage display libraries, Hana Golding and colleagues identify the viral epitopes recognized by serum antibodies in humans who have recovered from infection with H5N1 avian influenza.
Cell | 2001
Antonio Lanzavecchia; Federica Sallusto
membrane rafts containing kinases and adapters to the Immune responses are initiated in the T cell areas of synapse and amplifies up to 100-fold the signaling prosecondary lymphoid organs, where naı̈ve T lymphocytes cess initiated by the TCRs. Thus, in the absence of encounter dendritic cells (DCs) that present antigens costimulation, naive T cells can be activated only by taken up in peripheral tissues or locally. Antigens that extremely high (nonphysiologic) doses of antigens and do not have access to DCs are thus ignored by T cells, require a prolonged stimulation. In contrast, in the preswhile those that do have access to DCs can stimulate ence of costimulation, they can respond to 100-fold naı̈ve T cells, driving their proliferation and differentialower doses of antigen and also more rapidly. Detion or, in special circumstances, their deletion. Thus, pending on the antigen dose and level of costimulation, DCs represent the interface between the universe of naı̈ve T cells require 6 to greater than 30 hr of TCR foreign and tissue-specific antigens and T lymphocytes stimulation to reach commitment, while memory/effecand are the key players in the regulation of cell-mediated tor T cells respond within 0.5 to 2 hr. immunity. Once committed to the first division, T cells proliferate In this review, we will discuss how DCs provide a rapidly in response to IL-2, which is produced by actiquantitative and qualitative framework for T cell antigen vated T cells and can act in autocrine and paracrine recognition. We will first summarize the requirements fashions. Since IL-2 production is induced by antigenic for activation and differentiation of naı̈ve T cells in terms stimulation and is greatly enhanced by costimulation, of peptide-MHC complexes, costimulatory molecules, its availability in T cell areas varies widely as a function and cytokines. Then, we will consider how DCs assemof the extent and duration of T cell activation. ble these components into discrete packets that are There is growing evidence that the duration of TCR delivered to the T cell areas. Finally, we will discuss how stimulation, together with polarizing cytokines, deterthe density and quality of antigen-carrying DCs might mines the progressive differentiation of CD4 T cells, determine the magnitude and class of T cell responses. leading to the generation of terminally differentiated efRequirements for Activation and Differentiation fector cells as well as intermediates (Lanzavecchia and of Naı̈ve T Lymphocytes Sallusto, 2000). CD4 T cells that receive a short TCR To recognize antigen, T cells need to establish contact stimulation in the absence of IL-12 proliferate but do with antigen-presenting cells (APCs) by forming an imnot differentiate to effector cells. Upon in vivo transfer, munological synapse, where T cell receptors (TCRs) and they home to the lymph nodes and, following secondary costimulatory molecules are congregated in a central antigenic challenge, differentiate to effector cells. In area surrounded by a ring of adhesion molecules (Dustin contrast, T cells that receive a prolonged TCR stimulaand Cooper, 2000). At the synapse, a serial TCR trigtion in the presence of IL-12 or IL-4 terminally differentigering by peptide-MHC complexes initiates a signaling ate to Th1 cells, producing IFN, or to Th2 cells, produccascade of which the magnitude and duration determine ing IL-4, IL-5, and IL-13. As part of their differentiation the entry of naı̈ve T cells into the cell cycle. Synapses program, Th1 and Th2 cells lose the lymph node homing form within minutes after TCR triggering and are stable receptors and acquire the capacity to migrate to inin the absence of disturbing events, but can be disrupted flamed nonlymphoid tissues to execute their effector by cell division, death of APCs, or by external influences, functions. The progressive differentiation model is supsuch as collagen. It is important to consider that T cells ported by the existence of a distinct population of cenare continuously poised to form better synapses and tral memory T cells that lack immediate effector function can rapidly shift from one APC to another, offering a and carry the lymph node homing receptor CCR7. higher level of stimulation. Recent experiments indicate that, once commitment The amount of signal that T cells receive is dependent has been reached, CD8 T cells can autonomously dion three factors: (1) the level of peptide-MHC complexes vide (at least 7 times) and acquire cytotoxic function in that initiate signal transduction, (2) the level of costimuthe absence of further antigenic stimulation (Kaech and latory molecules that amplify the signaling process, and Ahmed, 2001; van Stipdonk et al., 2001). These findings (3) the stability of the synapse that determines for how imply that the clonal expansion and differentiation prolong the signaling process is sustained (Lanzavecchia grams are imprinted in naı̈ve CD8 T cells during a short and Sallusto, 2001). The efficiency of the synapse as a encounter with APCs, a fact that may reflect a higher signal transducing machinery varies with the nature of propensity to undergo terminal differentiation. It is unthe APC and the T cell’s developmental stage. In acticlear, however, which stimuli may control the generation
Immunology Today | 1998
Federica Sallusto; Antonio Lanzavecchia; Charles R. Mackay
Abstract T-cell priming occurs in the lymphoid tissue via T cell–dendritic cell interaction. Conversely, delayed-type hypersensitivity or allergic reactions can occur in any tissue, following interaction of T helper 1 (Th1) or Th2 cells with effector leukocytes. Here, Federica Sallusto and colleagues review the role played by chemokines and chemokine receptors in positioning T cells for the immune response.