25 January 2016 Cancer immunotherapy from the nanoscale

Super-resolution images of CD1d nanoclusters before (upper) and after (below) inflammatory stimulation.

A new mechanism to regulate activation of Natural Killer T cells in PNAS Plus Researchers Juan Torreno-Pina and Carlo Manzo working in the Single Molecule Biophotonics group led by ICREA Professor at ICFO Maria Garcia-Parajo, have recently discovered a novel mechanism that leads to the activation of Natural Killer T (iNKT) cells. After activation, iNKT cells play a crucial role in the initiation of immune responses against pathogens and cancer. The results provide crucial insights towards the development of immunotherapies against cancer and autoimmune diseases. The research has been performed in collaboration with the group of Prof. Melike Lakadamyali at ICFO and Prof. Enzo Cerundolo, Director of the Human Immunology Unit, The Weatherall Institute of Molecular Medicine at the University of Oxford (UK). It was published in PNAS Plus.

iNKT cells are a subset of T lymphocytes that can enhance or suppress immune responses through the rapid release of signaling molecules (cytokines) after stimulation through their T cell receptor. For iNKT cells to work, they need to become activated by a specific molecule, called CD1d, expressed on antigen presenting cells. Exogenous (resulting from micro-organisms or pathogens) lipids loaded to CD1d will activate iNKT cells to trigger a correct immune response, i.e., the destruction of the invader. Interestingly, endogenous lipids loaded to CD1d can also activate iNKT cells. This process is known as autoreactivity. How iNKT cell autoreactivity is fine-tuned to prevent or enhance immune responses remains a mystery.

Together with Oxford collaborators, the ICFO team showed that iNKT cell activation is regulated by the lateral nanoscale organization of CD1d loaded with exogenous and endogenous antigens. Using a combination of super-resolution imaging and dual color single particle tracking approaches, we showed that CD1d molecules organize in nanoclusters on the membrane of antigen presenting cells. We further discovered that the actin cytoskeleton prevents enhanced CD1d nanoclustering by hindering physical encountering between CD1d diffusing nanoclusters, reducing basal iNKT cell activation. As such, regulation of CD1d nanoclustering through the actin cytoskeleton constitutes a novel mechanism to fine tune peripheral iNKT cell autoreactivity. The observation that a similar actin-dependent mechanism regulates presentation of exogenous lipids and self-lipids on inflammatory stimuli further adds to the uniqueness of the CD1d-iNKT cell system in bridging innate and adaptive immune responses.

This study underscores the importance of emerging concepts, such as protein nanoclustering, in deepening our understanding of how leukocytes can modulate at the molecular level, the outcome of an immune reaction. We predict that this type of studies will provide essential information for the development of groundbreaking immune-based therapeutic strategies against autoimmune diseases and within the frontier field of cancer immunotherapy.

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