Research

Orchestration of immune synapse assembly by ciliary proteins

The immune synapse (IS) is a specialized membrane domain that forms at the interface of a T cell with an antigen presenting cell displaying cognate MHC-associated peptide antigen. The IS acts as a platform where signaling pathways triggered by the T cell antigen receptor, integrins and co-stimulatory/co-inhibitory receptors are coordinated to orchestrate the process of T cell activation and differentiation. We have uncovered a key role for ciliopathy-related proteins at different steps of IS assembly in the non-ciliated T cell, highlighting the IS as a functional homologue of the primary cilium. We are capitalizing on the significant body of knowledge of the mechanisms that regulate ciliogenesis to identify shared molecular players, with the aim to translate these findings to primary immunodeficiencies of unknown aetiology.

Regulation of SMAP biogenesis in cytotoxic T cells

Supramolecular attack particles (SMAPs) are newly discovered killing entities produced by cytotoxic T cells (CTLs), which are responsible for the elimination of transformed or virally-infected cells. SMAPs are characterised by an unusual composition consisting in a core of components of the "classical" killing machinery associated with lytic granules -granzymes, perforin and serglycin- encased in a glycoprotein shell. SMAPs, wich are released at by CTLs at the is formed with target cells. The pathways that regulate the biogenesis, release and uptake of SMAPs are at present unknown. We are investigating the mechanism of SMAP biogenesis, with a focus on the vesicular trafficking pathways that regulate the transport of the individual components, with the aim to engineer them for cancer specificity.

Mechanisms of T cell suppression in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasia characterized by the accumulation of abnormally long-lived CD5+ B cells in peripheral blood. Peripheral lymphoid organs, through which leukemic B cells transit cyclically, are central players in the pathogenesis of CLL, as they represent the tumor microenvironment (TME) which provides survival and proliferation signals and contributes to chemoresistance. Together with clinicians we are investigating the interplay of leukemic cells with the cellular components of the TME, with a focus on stromal cells and CTLs, to understand how CLL cells condition the TME to attract and retain leukemic cells in the pro-survival and protective lymphoid niche while evading CTL-mediated killing. We are addressing the impact of a defect of the pro-oxidant adaptor p66Shc in CLL cells on their ability to modify the TME to promote disease progression.

Cross-talk of astrocytes with of immune and neuronal cells in multiple sclerosis and glioblastoma

Multiple sclerosis is an autoimmune disease characterized by the development of myelin-specific inflammatory Th17 and Th1 cells that cross the blood-brain barrier and promote local inflammation of the CNS, eventually leading to neurodegeneration. As components of the blood-brain barrier, astrocytes are the first cells encountered by infiltrating encephalitogenic T cells. Additionally, astrocytes modulate the TME in the context of glioblastoma by releasing soluble and EV-associated mediators that affect tumoral cell growth and invasiveness. We are investigating the EV-mediated mechanisms that participate in the cross-talk of astrocytes with encephalitogenic T cells and glioblastoma cells, with a recent focus of non-membranous nanoparticles that appear structurally related to SMAPs.