What is this research project about?
Figure 1: Amplicon sequencing of expressed antigen receptors (click image to enlarge)
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.
Figure 2: Amplicon sequencing of expressed antigen receptors (click image to enlarge)
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.