Dynamics of the T cell receptor repertoire of a small vertebrate in response to infection
The adaptive immune system of vertebrates is central to defense against pathogens. It relies on T cells, which respond to pathogenic exposure via T cell receptors (TCRs) recognizing antigens presented by Major Histocompatibility Complex (MHC) molecules. MHC variability and TCR repertoire diversity are crucial for the initiation and efficacy of the adaptive immune response, respectively. Building upon recent advancements in TCR repertoire analysis using Next Generation Sequencing (NGS), this thesis explores the TCR repertoire dynamics during infection in the three-spined stickleback, an experimental model species encompassing natural genetic variation. Chapter 1 focuses on developing a reproducible NGS-based protocol for reliable MHC genotyping, and highlights the importance of pipeline optimization for accurate allele expression analysis via use of DNA and RNA data. Chapter 2 investigates the TCR repertoire in response to controlled helminth infection, and demonstrates significant non-MHC genetic effects on its diversity. Hints of parasite-induced suppression of TCR compartments are discussed in an eco-evolutionary context. Public, MHC-unrestricted TCRs provide indirect evidence for previously uncharacterized non-conventional T cells. Lastly, Chapter 3 examines the TCR repertoire in a semi-natural setting, following stickleback exposure to its natal environment. Findings include robust TCR activation coinciding with multiple infections, and notable sex-based differences in repertoire diversity. Age-related changes in repertoire composition align with known mammalian aging patterns. Overall, this thesis advances our understanding of TCR repertoire infection dynamics, emphasizing strong genetic and environmental factors shaping its diversity. This work also offers insights into a mode of TCR repertoire organization conserved throughout vertebrate evolution, based on innate-like T cells, the functional importance of which is yet to be fully elucidated.
Preview
Rights
Use and reproduction:
Please note that individual components of the publication may be subject to other licensing or copyright conditions.