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NCKIR2: Function of CD8 T Cell communication during autoimmunity.


   Kennedy Institute of Rheumatology

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  Dr A Gérard, Prof M Dustin  No more applications being accepted  Funded PhD Project (Students Worldwide)

Oxford United Kingdom Immunology

About the Project

We are interested in understanding how cells of the adaptive immune system, called CD8 T cells, are recruited and organised in space and time in vivo in health and disease (1,2). CD8 T cells are plastic and heterogenous; however, their overall, collective response to pathogens is consistent and robust, resulting in efficient pathogen eradication while preserving tolerance (3,4). To achieve this level of global coordination, T cells have to communicate and co-regulate each other. We recently discovered that CD8 T cells interact with each other by forming T cell–T cell synapses (1,5), using the integrin LFA-1 and its ligand ICAM-1. The current hypothesis is that T cells form T-T synapses to specifically share cytokines with each other. We identified IFNg as one key cytokine mediating T cell communication at T-T synapses (6). During infection, IFNg limits cytotoxic CD8 T cell differentiation and enhances memory formation (6).

IFNg, LFA-1, ICAM-1 and associated genes have all been implicated in mouse models of autoimmune diseases such as diabetes or lupus. In addition, Single nucleotide polymorphism (SNP) in those genes have been linked to many diverse autoimmune disorders in humans (such as Rheumatoid Arthritis, Lupus, Type 1 Diabetes…), suggesting a pivotal and general role of these proteins in regulating tolerance. Whether it is at least partly related to direct T cell communication is unknown.

This project will investigate how direct interactions between CD8 T cells, by controlling T cell collective responses, control the balance between immunity and tolerance. Our main hypothesis is that T cell communication prevents autoimmune reactions while enabling pathogen-specific responses. This project is based on prohibiting cell interactions between CD8 T cells, using cell-specific KO mice. The candidate will analyse whether inhibiting T-T interactions affects immune responses, focusing on susceptibility to autoimmune diseases, such as Type 1 Diabetes or Vitiligo. To characterise the function of T cell communication, you will use mouse models of autoimmunity and/or infection, cutting edge imaging and conventional immunological assays such as flow cytometry.

These studies will identify mechanisms used by CD8 T cells to co-regulate their response to ultimately maintain the balance between immunity and tolerance.

Training Opportunities:

The Kennedy Institute is a world-renowned research centre and is housed in a brand-new state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques, and imaging. A core curriculum of 20 lectures will be taken in the first term of year one to provide a solid foundation in immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Students will also attend external scientific conferences where they will be expected to present the research findings.


References

KEY Publications
1. Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Gérard et al (2014), Cell, 158, 492 – 505.
2. Modes of Communication between T Cells and Relevance for Immune Responses. Uhl et al (2020), IJMS, 21(8), 2674.
3. Quorum Regulation via Nested Antagonistic Feedback Circuits Mediated by the Receptors CD28 and CTLA-4 Confers Robustness to T Cell Population Dynamics, Zenke. et al (2020), Immunity 52(2):313-327.e7.
4. Evolving immune circuits are generated by flexible, motile, and sequential immunological synapses. Gérard A. et al, (2013), Immunol Rev, 251, 80 - 96.
5. Paracrine Costimulation of IFN gamma Signaling by Integrins modulates CD8 T cell differentiation. Mahale, Krummel et al, (2018) PNAS, 115(45):11585-11590.
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