Biology subjects

Härtle, S.

Publications and source records attributed to Härtle, S..

2 recordsLinked to original sources

bioRxiv2023

Unraveling the role of γδ T cells in the pathogenesis of an oncogenic avian herpesvirus

Mareks disease virus (MDV) is an oncogenic alphaherpesvirus that causes deadly T cell lymphomas in chickens. MDV is highly cell associated which allows the virus to evade antibody-mediated virus neutralization. Therefore, T cell-mediated immune responses are thought to be crucial for combating this deadly pathogen. In chickens, gamma delta ({gamma}{delta}) T cells represent a major population with up to 50% of all peripheral T cells. However, their role in MDV pathogenesis and tumor formation remains poorly understood. To investigate the role of {gamma}{delta} T cells in MDV pathogenesis, we infected genetically modified chickens that lack {gamma}{delta} T cells (TCR C{gamma}-/-) with very virulent MDV. Strikingly, disease and tumor incidence were highly increased in the absence of {gamma}{delta} T cells, indicating that {gamma}{delta} T cells play an important role in the immune response against MDV. In the absence of {gamma}{delta} T cells, virus replication was increased by up to 89-fold in the thymus and spleen, both potential sites of T cell transformation. Taken together, our data provide the first evidence that {gamma}{delta} T cells play an important role in restricting MDV replication, pathogenesis and tumors caused by this deadly pathogen. Author Summary{gamma}{delta} T cells are the most abundant T cells in chickens, but their role in fighting pathogens remains poorly understood. Mareks disease virus (MDV) is an important veterinary pathogen, causes one of the most frequent cancers in animals and is used as a model for virus-induced tumor formation. Our study revealed that {gamma}{delta} T cells play a crucial role in combating MDV, as disease and tumor incidence was drastically increased in the absence of these cells. {gamma}{delta} T cells restricted virus replication in the key lymphoid organs, thereby decreasing the likelihood of causing tumors and disease. This study provides novel insights into the role of {gamma}{delta} T cells in the pathogenesis of this highly oncogenic virus.

microbiology↗

bioRxiv2020

Differential host response to a herpesvirus: Mareks disease virus peptides on chicken MHC class II molecules are derived from only a few genes and illustrate a new mode of peptide binding

Viral diseases pose major threats to humans and other animals, including the billions of chickens that are an important food source as well as a public health concern due to zoonotic pathogens. Unlike humans and other typical mammals, the major histocompatibility complex (MHC) of chickens can confer decisive resistance or susceptibility to many viral diseases. An iconic example is Mareks disease, caused by an oncogenic herpesvirus with over 100 genes. Classical MHC class I and class II molecules present antigenic peptides to T lymphocytes, and it has been hard to understand how such MHC molecules could be involved in susceptibility to Mareks disease, given the potential number of peptides from over 100 genes. We used a new in vitro infection system and immunopeptidomics to determine peptide motifs for the two class II molecules expressed by the MHC haplotype B2, which is known to confer resistance to Mareks disease. Surprisingly, we found that the vast majority of viral peptide epitopes presented by chicken class II molecules arise from only four viral genes, nearly all having the peptide motif for BL2, the dominantly-expressed class II molecule in chickens. We expressed BL2 linked to several MDV peptides, and determined one X-ray crystal structure, showing how a single small amino acid in the binding site causes a crinkle in the peptide, leading to core binding peptide of ten amino acids, compared to the nine amino acids in all other reported class II molecules. The limited number of potential T cell epitopes from such a complex virus can explain the differential MHC-determined resistance to MDV, but raises questions of mechanism and opportunities for vaccine targets in this important food species, as well as providing a basis for understanding class II molecules in other species including humans.

immunology↗