Molecular control of γδ T cell development
γδ T cells can be classified through expression of the given γ- and δ -chains of their γδ T cell receptor (TCR) complex and their localization within the body. γδ T cells can arise in the very early embryonic developmental phase, have a high level of functionality and are therefore an important part of the early childhood immune system. Presumably, the γδ T cell development in the thymus and the functional maturation is regulated by a complex interplay of extrinsic (e.g.
TCR signals) and intrinsic (e.g. transcription factors) mechanisms.
In the mouse, interleukin 17-producing γδ T cells develop within an embryonic thymus and are maintained as long-living, tissue-resident cells throughout adulthood. In the first part of this project we investigated the longevity and tissue-specific adaptation of IL17+ γδ T cells at the transcriptional level and identified molecular differences between IL17+ Vγ4 and Vγ6 T cells. We believe that these molecular differences arise during the initial development and functional pre-priming during the initial thymic development. In the first part of the proposed project, we apply next-generation sequencing based methods to understand underlying transcriptional and epigenetic program of Vγ4 amd Vγ6 T cell during their formation and add another dimension: age. Together with working groups of the FOR, we aim at understanding the influence of TCR signals on their development and functional maturation.
During the first funding period we studied the postnatal maturation of human γδ T cells and identified fetal-derived Vγ9Vδ2 T cells undergoing microbial-induced proliferation immediately after birth. Notably, neonatal and adult Vγ9Vδ2 T cells largely differ in TCR repertoire compositions and the capability to mature and proliferate after TCR-dependent activation. Now in the second part of the project we aim at understanding how TCR activation impacts on the functional maturation of Vγ9Vδ2 T cells, how this is controlled at transcriptional level and how this differs among neonates and adults. Within the FOR we aim at further identifying common dominators of Vγ9Vδ2 T cells between camelids and humans.
This proposed project is part of the research group FOR 2799 („Receiving and Translating Signals via the γδ T Cell Receptor“) and will benefit from collaborations with other projects within the research group.
Molecular control of γδ T cell functions
γδ T cells can be classified through expression of the given γ- and δ -chains of their γδ T cell receptor (TCR) complex and their localization within the body. As innate T lymphocytes they are already at birth highly functional and may immediately protect newborns against pathogenic infections. We assume that extrinsic (self-antigens, microbial exposure) and intrinsic (transcription factors) factors might fine-tune the development, organ-specificity and functional adaptation of murine and human γδ T cells.
Murine IL-17 producing Vγ6 and Vγ4 T cells develop within an embryonic thymus and are maintained as long-living, tissue-resident cells throughout adulthood. In the first part of this project we aim at understanding how the adaptation and maintenance of IL-17 producing γδ T cells is regulated through underlying transcriptional mechanisms. We will apply single-cell RNA sequencing (single-cell RNA-seq) technologies and bioinformatics to analyze and compare the heterogeneity and transcriptional differences of tissue-specific IL-17 producing γδ T cells.
In the second part of this project we characterize the functional adaptation of human γδ T cells in neonates and adults. We and other could recently show by next generation sequencing of human γδ TCRs that adult, but not neonatal, γδ TCR repertoires display a high diversity and consist of individual, expanded γδ T cell clones. We hypothesize that innate γδ T cells are a first set of standard effector cells and are only present in early childhood. Now we aim at understanding how the expansion of individual γδ T cell clones throughout life is reflected and controlled through gene expression and epigenetic programs.