Regulation of Treg localisation during infection

Project No: Clinical-10
Intake: 2024 KIR Clinical

PROJECT OVERVIEW

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). 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 (2,3). To achieve this level of global coordination, T cells have to both co-regulate each other by forming T cell–T cell synapses (1,4), while sensing and integrating information from their environment.

We recently discovered that even within the same tissue, and in response to the same trigger, multiple contrasting microenvironments, or niches, form. Following Listeria infection, T cell priming occurs in at least two niches. One niche is characterised by NK cells and the inflammatory cytokine IFNg. In this niche, we discovered that IFNg is used by T cells to communicate and enhance the generation of a strong memory response (4,5). Interestingly, we observe another microenvironment during Listeria infection which is characterised by the presence of Tregs, a regulatory CD4 T cell subset that is known to suppress immune responses, thereby maintaining homeostasis and self-tolerance. The function of Tregs during infection is unclear, but current studies suggest that Tregs limit the efficacy of the CD8 T cell response. Therefore, their exclusion from the highly inflammatory niche is likely to be crucial to elicit a strong and efficient immune response, and as such their spatio-temporal dynamics must be tightly regulated.

The goal of this project is to identify the importance of Treg segregation during infection, and explore the mechanism by which Tregs are excluded from the highly inflammatory environment. To do so, you will use conventional immunological assays, and rely on multiple microscopy techniques such as confocal and 2-photon imaging.

This study will identify how Tregs are excluded from the inflammatory niche during infection, and the relevance of this spatial regulation. Given the importance of Tregs for tolerance and autoimmune diseases, understanding how Tregs are spatially segregated to allow for a cytotoxic immune response to be elicited could have therapeutic implications if we understand how this can be manipulated, for example during autoimmune diseases.

KEYWORDS (5 WORDS)

Tregs, CD8 T cells, infection, imaging

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility, including flow cytometry and imaging. 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 1 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.

KEY PUBLICATIONS (5 maximum)

(1) Secondary T cell-T cell synaptic interactions drive the differentiation of protective CD8+ T cells. Gérard et al (2013), Nat Immunol, 14, 356 – 363.

(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) Paracrine Costimulation of IFN gamma Signaling by Integrins modulates CD8 T cell differentiation. Mahale, Krummel et al, (2018) PNAS, 115(45):11585-11590.

(5) Lion F.K. Uhl, Han Cai, Jagdish N. Mahale, Andrew J. MacLean, Julie M. Mazet, Alexander J. He, Doreen Lau, Tim Elliott, and Audrey Gérard. Integration of Avidity and Differentiation is enabled by CD8+ T-cell sensing of IFN-γ, preprint (10.1101/2023.03.06.531375)