Tracking adaptation of naïve T cells to distinct organs to decode organ-specific immune diseases

Introduction

Organ-specific immune-mediated inflammatory diseases (IMIDs) have a growing socio-economic impact due to their steadily increasing incidence. At least two aspects are still unclear: what immunological mechanisms restrict these diseases to one or a set of specific organs and what triggers the continuously increasing incidence, particularly in industrialized countries.

Environmental Triggers

Increasing exposure to harmful environmental triggers, such as pollution and the Western diet, have been suggested as potential reasons. We propose that when locally active immune cells are perturbed by harmful environmental triggers, this leads to organ-specific IMIDs.

Naïve CD4+ T Cells

Naïve CD4+ T cells have so far been considered a quasi-homogenous and inert population excluded from organs. Therefore, their contribution to organ-specific IMIDs has been overlooked. Contrary to this, there is evidence that naïve T cells circulate through organs and diversify into different subpopulations reflecting the organ they patrol.

Project Aims

This project aims to reveal whether organ adaptation of naïve T cells in steady state is one of the key mechanisms contributing to the organization of the immune system into districts of competence - i.e., areas of inflammation. We also aim to understand whether organ-specific naïve T cells responding to harmful environmental triggers set the early premise for the development of organ-specific IMIDs.

Methodology

We will study this using a unique portfolio of healthy and diseased human organs in combination with multi-modal single-cell technologies to gain an unprecedented resolution in the analysis of naïve T cells. Next, we will use mouse models and 3D human co-cultures to test naïve T cell function and response to environmental triggers.

Impact

This project will influence the current understanding of how the activity of the immune system is adapted and distributed throughout the body, which will also push the boundary of precision medicine to consider organ-specific naïve T cells when designing future immunotherapies.