Microbiota-T cell interactions - antigen-specificity and regulation in health and disease

Introduction

The microbiota has an enormous influence on human health. CD4+ T cells play a central role in controlling the interaction with the microbiota. By specifically reacting against individual microbial species, T cells enable a mutualistic co-existence with microbes. Inappropriate T cell responses against microbes are in turn associated with inflammatory diseases.

Importance of T Cell Specificity

Thus, the combination of T cell specificity and functionality forms the key determinant for physiological versus pathological host-microbiota interactions. So far, research on T cell-microbiota interaction is almost exclusively focused on functional T cell subsets, whereas antigen-specificity is rarely addressed. This is a significant roadblock for developing targeted therapeutic interventions for microbiota-associated diseases.

Challenges in Adaptive Immunity

The interaction with the microbiota poses two particular challenges for adaptive immunity:

1. The extremely high diversity of microbial species, and thus potential T cell targets.
2. Microbes are persistent and thus probably encountered chronically.

Currently, we do not know:

1. Which microbes are targets of specific T cell reactivity in humans.
2. How the (chronic) interaction with the huge number of different microbial species is regulated by T cell specificity and function.
3. How alterations of these parameters contribute to microbiota-associated diseases.

Proposed Solution

I developed a highly sensitive technology to detect and deeply characterize microbe-specific T cells directly from human samples. MicroT will identify microbial target species of human T cells and unravel the molecular mechanisms regulating chronic interaction of T cells with the highly diverse microbiota.

Research Goals

I will define the impact of specific T cell-microbiota interactions on chronic inflammatory diseases and upon ageing. Answering these fundamental questions of microbiota-T cell interaction will identify specific immune or microbial targets as an essential basis for the rational development of novel targeted therapies.