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

What is this research project about?

Professorin Viemann, Dr. Fichtner, Professorin Ravens und Professor Prinz (von links) mit Reagenzien für die Sequenzierung der T-Zell-Rezeptoren

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 and immune status of preterm babies differs from that of term infants. This project focuses 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 life-long susceptibility towards infectious diseases.

Figure 1: In order to analyze the expressed T cell receptor from isolated gamma delta T cells, antigen binding sites (CDR3 regions) are amplified via a gene specific primer after reverse transcription. PCR amplicons are then subjected to high-throughput sequencing.

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.

Figure 2: Bioinformatic analysis of sequencing data. The sequencing readings obtained are annotated to the V(D)J regions of the antigen receptors to finally analyze and visualize the diversity of antigen receptor repertoires within defined samples.

Amplicon sequencing of expressed antigen receptors (click image to enlarge)

What are the project goals?

In this project we aim to understand how a defined microbiota, but also infections may influence the individual responsiveness and antigen-receptor repertoires of γδ T cells, αβ T cells and B cells against pathogens in infants. 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?

The RG Ravens and RG Prinz have recently 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.

Similarly, RG Viemann found a profound reprogramming and imprinting of cellular and molecular innate immunity in healthy infants during the first year of life that is driven by endogenous as well as environmental triggers (Austermann et al., 2014; Heinemann et al., 2017; Ulas et al., 2017; Pirr et al., 2017; Bickes et al., 2019).

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. Within RESIST, we combine our expertise and jointly continue the work on how a defined microbiota influences the functional maturation of T cells and B cells within preterm infants and how the expressed antigen-receptor repertoire is shaped during early life.

High-throughput analysis of antigen receptor repertoires (click image to enlarge)


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

Prof. Dr. Dorothee Viemann

Projekte: B1, B3

CV & Contact

Prof. Dr. Sarina Ravens

Projekte: B3, B5

CV & Contact

Project B3 Publications

Microbial exposure drives polyclonal expansion of innate gd T cells immediately after birth. Sarina Ravens, Alina S. Fichtner, Maike Willers, Dennis Torkornoo, Sabine Pirr, Jennifer Schöning, Malte Deseke, Inga Sandrock, Anja Bubke, Anneke Wilharm, Daniel Dodoo, Beverly Egyir, Katie L. Flanagan, Lars Steinbrück, Paul Dickinson, Ghazal, Adu, Dorothee Viemann, Immo Prinz. PNAS August 4, 2020 117 (31) 18649-18660; first published July 20, 2020 https://doi.org/10.1073/pnas.1922588117

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. doi: 10.1002/JLB.1MA0120-427RR

Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites. Bickes, M.S., S. Pirr, A.S. Heinemann, B. Fehlhaber, S. Halle, L. Völlger, M. Willers, M. Richter, C. Böhne, M. Albrecht, M. Langer, S. Pfeifer, D. Jonigk, G. Vieten, B. Ure, C. von Kaisenberg, R. Förster, M. von Köckritz-Blickwede, G. Hansen, D. Viemann. FASEB J., 2019, [Epub ahead of print] doi: 10.1096/fj.201900796R.

Project B3