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Seminar

Monday, March 8th, 2021
11h30
Teams - https://teams.microsoft.com/l/meetup-join/19%3ameeting_ZDM1ZDgyNjAtMTU3Yi00ZWU3LWFmMzgtZjJiNGIzYjZlYjNl%40thread.v2/0?context=%7b%22Tid%22%3a%22183ad437-6002-48ad-8886-c5885ce9be1a%22%2c%22Oid%22%3a%22a8544e4e-fdf2-4f3e-9c14-1678560c1a02%22%7d

The immunological synapse in the attack against cancer and infection

M Dustin

Follicular Helper T cells, Cytotoxic T cells (CTL) and Natural Killer (NK) cells are effectors of the immune system that play important roles in defense against viral infection and cancer.   In this talk I will present four vignettes related to biophysical exploration of effector immunological synapses with relevance to infection or cancer.

Early studies of the immunological synapse revealed a canonical architecture with a striking accumulation of T cell receptor (TCR) in the center driven by actin cytoskeleton and endosomal sorting complexes required for transport (ESCRT). The ESCRT machinery can mediate in situ conversion of TCR microclusters into extracellular vesicles we refer to as synaptic ectosomes. We have shown that one function of synaptic ectosomes is the provision of highly active CD40 ligand clusters, which is a key effector molecule of helper T cells.  I will provide an update on in vivo evidence for synaptic ectosome function.

The second topic relates to the role of the adhesion molecule CD2- which mediates “liquid” adhesions. I will describe how CD2, the receptor for CD58 on T cells, contributes to signal amplification that CD2 expression is often low in “exhausted” CD8 tumor infiltrating lymphocytes in several types of cancer, although the regulation of CD2 seems to be distinct from other exhaustion associated receptors like PD1, with which CD2 is highly miscible.

The third topic is the role of Plasmodium falciparum RIFINs to mimic natural inhibitory ligands for cytotoxic effector cells.  Red blood cells have long been known to express CD58, leading the historically important erythrocyte rosetting test for T cells.  The importance of erythrocytes as hosts for Plasmodium falciparum may provide a rationale for retention of T/NK adhesion molecules on the terminally differentiation, enucleated cells.

The fourth topic is the new discovery of cytotoxic bombs deployed by CTL and NK cells against targets.  CTL and NK cells assemble cytotoxic proteins into supramolecular attack particles (SMAPs) with a core of perforin and granzymes and a shell of thrombospondin-1.  I will introduce what we know about these novel entities.  We also show that CD2-CD58 interaction promotes the release of SMAPs into the synapse.

In summary, the biophysical analysis of immunological synapses with supported lipid bilayers continues to generate insights into T cell effector mechanisms.

Speaker(s)

Michael L Dustin

University of Oxford, UK

Invited by

Claire Hivroz
Domain 3 - U932 - Immunity and Cancer

Institut Curie

Nicolas Manel
Domain 3 - U932 - Immunity and Cancer

Institut Curie

Learn more

Prof. Dustin has a B.A. in Biology from Boston University (1984) and a Ph.D. in Cell and Developmental Biology from Harvard University (1990). He studied glucose transport in red blood cells for his undergraduate thesis with Scott W. Peterson and studied biochemistry and regulation of lymphocyte adhesion molecules during his PhD with Timothy A. Springer. He completed post-doctoral training with Stuart Kornfeld on lysosome structure and function at Washington University School of Medicine (1993). Dr. Dustin led his own group at the Department of Pathology at Washington University School of Medicine under Steve Teitelbaum and Emil Unanue from 1993 to 2000. While at Wash U, he led a collaborative group in discovering requirements for the T cell immunological synapse with Andrey Shaw, Paul Allen, Mark Davis (Stanford) and Emil Unanue. He moved his lab to the Skirball Institute of Biomolecular Medicine at New York University School of Medicine in 2001. He collaborated on new intravital microscopy projects with Wenbiao Gan, Dan Littman, Juan Lafaille, Michel Nussensweig, Dorian McGavern and Sandra Demaria among others. Continuation of work on the immunological synapse led to a basic description of the supramolecular assemblies that make up the mature immunological synapse. Specialized functions of the immunological synapse in cytotoxic T cells and regulatory T cells were also explored. This work includes the recent observation that the small vesicles enriched in T cell receptor, synaptic ectosomes, are directly budded into the immunological synapse, handing off T cell receptor and other cargo to the antigen presenting cell. He was director of the NIH funded Nanomedicine Center for Mechanobiology from 2009-2014 In order to further advance studies on the immunological synapse and translation to treatment of human diseases he moved to the Kennedy Institute of Rheumatology at the University of Oxford in 2013 supported by a Principal Research Fellowship from the Wellcome Trust.