Which impact do intestinal bacteria and infections have on the fitness of immune cells?

What is this research project about?

The project is based on the PRIMAL cohort. It is used to investigate the susceptibility to infections of premature babies in the first year of life after the administration of probiotics in the first weeks of life. We are investigating the maturation of T-cells and B-cells.

What is this research project about?

Infections are one of the main risks leading to neonatal morbidity and mortality of preterm infants. There is little information on how the immune cell maturation is impacted by health promoting factors like probiotica in preterm babies and how this differs from that of term infants.

In collaboration with Prof. Dr. Dorothee Viemann we aim at understanding immune cell maturation in a longitudinal cohort of preterm neonates that are supplemented with probiotics in the first weeks of life. In this project we focus on γδ T cells, αβ T cells and B cells, which are characterized by the expression of an antigen receptor. These immune cell subsets can either directly contribute to the immunity in neonates, but the majority undergoes a postnatal maturation driven by microbial challenges to become fully functional. This early age-related and environment-dependent imprinting on the antigen receptor repertoire and functionality of T cells and B cells might impact on the individual’s immune status and susceptibility towards infectious diseases during early life.

This project is based on the PRIMAL cohort. Prof. Viemann is heading and coordinating the PRIMAL cohort, a double-blinded study to understand the impact of probiotics supplements in the first weeks on disease susceptibility within the first year after preterm birth. We focus on understanding postnatal maturation of T cells and B cells.

What’s the current status?

Directly after birth, environmental factors such as the microbiota colonizing mucocutaneous barrier sites, but also occurring infections are important for the maturation of the children’s immune system. These host-pathogen interactions individually shape and imprint the immune system during early life. However, which environmental cues drive the adaptation of γδ T cells, αβ T cells and B cells with respect to their functionality and antigen-receptor repertoire after birth and how this might differ between preterm and term babies remains largely unclear.

To the picture: Age-dependent differences in antigen receptor repertoires. The Treemaps depict the abundance and distribution of individual T cell clones of γδ T cells in the peripheral blood of a newborn and an adult. Each square represents the abundance of a T cell clones according to the square size. We would like to decipher the impact of intrinsic factors, infections and microbiota on the postnatal maturation of antigen-receptor repertoires during early life.

What are the project goals?

In this project we aim to understand how perinatal factors, probiotica and a defined microbiota may influence the individual responsiveness and antigen-receptor repertoires of γδ T cells, αβ T cells and B cells and their postnatal maturation within the first year after preterm birth. We further aim to identify new biomarkers to predict the susceptibility of individual patients against infectious diseases, which may finally improve current therapeutic strategies.

How do we get there?

We have developed an mRNA-based high-throughput analysis technology and bioinformatics methods to analyze T-cell receptor repertoires within neonates and adults (Ravens et al., 2017). Initial data of defined patient cohorts indicates (i) a postnatal, extrathymic maturation of T cells (Ravens et al., 2017; DiLorenzo et al., 2019) and (ii) that viral infections leave a sustained footprint within the antigen receptor repertoire (Ravens et al., 2017; Ravens et al., 2018). The latter results propose that antigen receptor repertoires might serve as valuable biomarkers. More recently, we found that defined T cells develop in the early human thymus and immediately expand in response to the microbiota after preterm birth (Ravens, Fichtner et al., 2020, Tan, Fichtner et al., 2021).

Altogether, these findings reflect the developmental plasticity and suggest options for an iatrogenic imprinting of innate and adaptive immunity to promote immune maturation and adaptation during early life in individuals at high risk for infection- and immune-mediated diseases. Together with RG Viemann (RESIST project B1) we work on how defined factors influence the functional maturation of T cells and B cells within preterm infants and how the expressed antigen-receptor repertoire is shaped during early life.

The sequencing reads obtained are annotated to the V(D)J regions of the antigen receptors to finally analyse and visualise the diversity of antigen receptor repertoires within defined samples.

Projectleader

Project title: Impact of probiotics on the maturation of immune cell repertoires in preterm infants

Prof. Dr. Sarina Ravens

Projekte: B3, B5

CV & VIDEO

Project B3 Publications

Publications of the Year 2022

Evidence for an Adult-Like Type 1-Immunity Phenotype of Vδ1, Vδ2 and Vδ3 T Cells in Ghanaian Children With Repeated Exposure to Malaria. León-Lara X, Yang T, Fichtner AS, Bruni E, von Kaisenberg C, Eiz-Vesper B, Dodoo D, Adu B, Ravens S. Front Immunol. 2022 Feb 17;13:807765

Publications of the Year 2021

Role of the gut microbiota in airway immunity and host defense against respiratory infections. Willers M, Viemann D. Biol Chem. 2021 Oct 4. doi: 10.1515/hsz-2021-0281. Epub ahead of print. PMID: 34599869.

A fetal wave of human type 3 effector γδ cells with restricted TCR diversity persists into adulthood. By Likai Tan, Alina Suzann Fichtner, Elena Bruni, Ivan Odak, Inga Sandrock, Anja Bubke, Alina Borchers, Christian Schultze-Florey, Christian Koenecke, Reinhold Förster, Michael Jarek, Constantin von Kaisenberg, Ansgar Schulz, Xiaojing Chu, Bowen Zhang, Yang Li, Ulf Panzer, Christian F. Krebs, Sarina Ravens, Immo Prinz. Science Immunology23 Apr 2021

Publications of the Year 2020

TCR repertoire analysis reveals phosphoantigen-induced polyclonal proliferation of Vγ9Vδ2 T cells in neonates and adults. Fichtner AS, Bubke A, Rampoldi F, Wilharm A, Tan L, Steinbrück L, Schultze-Florey C, von Kaisenberg C, Prinz I, Herrmann T, Ravens S. Journal of Leukocyte Biology Volume 107, Issue 6 2020 Feb 17.

S100-Alarmins Are Essential Pilots of Postnatal Innate Immune Adaptation. Viemann D. Front Immunol. 2020 Apr 30;11:688. doi: 10.3389/fimmu.2020.00688. PMID: 32425933; PMCID: PMC7203218.

S100A8 and S100A9 Are Important for Postnatal Development of Gut Microbiota and Immune System in Mice and Infants. Willers M, Ulas T, Völlger L, Vogl T, Heinemann AS, Pirr S, Pagel J, Fehlhaber B, Halle O, Schöning J, Schreek S, Löber U, Essex M, Hombach P, Graspeuntner S, Basic M, Bleich A, Cloppenborg-Schmidt K, Künzel S, Jonigk D, Rupp J, Hansen G, Förster R, Baines JF, Härtel C, Schultze JL, Forslund SK, Roth J, Viemann D. Gastroenterology. 2020 Dec;159(6):2130-2145.e5. doi: 10.1053/j.gastro.2020.08.019. Epub 2020 Aug 15. PMID: 32805279.

Host Factors of Favorable Intestinal Microbial Colonization. Pirr S, Viemann D. Front Immunol. 2020 Oct 7;11:584288. doi: 10.3389/fimmu.2020.584288. PMID: 33117398; PMCID: PMC7576995.

Publications of the Project B3