@phdthesis{Knoepper2022,
  author    = {Kn{\"o}pper, Konrad},
  title     = {Lymph node heterogeneity is imprinted by unconventional T cells that are organized in functional units},
  doi       = {10.25972/OPUS-29694},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296949},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {The immune system has the function to defend organisms against a variety of pathogens and malignancies. To perform this task, different parts of the immune system work in concert and influence each other to balance and optimize its functional output upon activation. One aspect that determines this output and ultimately the outcome of the infection is the tissue context in which the activation takes place. As such, it has been shown that dendritic cells can relay information from the infection sites to draining lymph nodes. This way, the ensuing adaptive immune response that is initiated by dendritic cells, is optimized to the tissue context in which the infection needs to be cleared. Here, we set out to investigate whether unconventional T cells (UTC) could have a similar function in directing a site-specific immune response. Using flow cytometry, scRNA-sequencing and functional assays we demonstrated that UTC indeed drive a characteristic immune response in lymph nodes depending on the drained tissues. This function of UTC was directly connected to their lymphatic migration from tissues to draining lymph nodes reminiscent of dendritic cells. Besides these tissue-derived UTC that migrated via the lymph, we further identified circulatory UTC that migrated between lymph nodes via the blood. Functional characterization of UTC following bacterial infection in wt and single TCR-based lineage deficient mice that lacked subgroups of UTC further revealed that both tissue-derived and circulatory UTC were organized in functional units independent of their TCR-based lineage-affiliation (MAIT, NKT, gd T cells). Specific reporter mouse models revealed that UTC within the same functional unit were also located in the same microanatomical areas of lymph nodes, further supporting their shared function. Our data show that the numbers and function of UTC were compensated in single TCR-based lineage deficient mice that lacked subgroups of UTC. Taken together, our results characterize the transcriptional landscape and migrational behavior of UTC in different lymph nodes. UTC contribute to a functional heterogeneity of lymph nodes, which in turn guides optimized, site-specific immune responses. Additionally, we propose the classification of UTC within functional units independent of their TCR-based lineage. These results add significantly to our understanding of UTC biology and have direct clinical implications. We hope that our data will guide targeted vaccination approaches and cell-based therapies to optimize immune responses against pathogens and cancer.},
  language  = {en}
}
@article{PetersKnoepperGrafenetal.2022,
  author    = {Peters, Annika E. and Kn{\"o}pper, Konrad and Grafen, Anika and Kastenm{\"u}ller, Wolfgang},
  title     = {A multifunctional mouse model to study the role of Samd3},
  series = {European Journal of Immunology},
  volume    = {52},
  journal   = {European Journal of Immunology},
  number    = {2},
  doi       = {10.1002/eji.202149469},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257362},
  pages     = {328-337},
  year      = {2022},
  abstract  = {The capacity to develop immunological memory is a hallmark of the adaptive immune system. To investigate the role of Samd3 for cellular immune responses and memory development, we generated a conditional knock-out mouse including a fluorescent reporter and a huDTR cassette for conditional depletion of Samd3-expressing cells. Samd3 expression was observed in NK cells and CD8 T cells, which are known for their specific function against intracellular pathogens like viruses. After acute viral infections, Samd3 expression was enriched within memory precursor cells and the frequency of Samd3-expressing cells increased during the progression into the memory phase. Similarly, during chronic viral infections, Samd3 expression was predominantly detected within precursors of exhausted CD8 T cells that are critical for viral control. At the functional level however, Samd3-deficient CD8 T cells were not compromised in the context of acute infection with Vaccinia virus or chronic infection with Lymphocytic choriomeningitis virus. Taken together, we describe a novel multifunctional mouse model to study the role of Samd3 and Samd3-expressing cells. We found that Samd3 is specifically expressed in NK cells, memory CD8 T cells, and precursor exhausted T cells during viral infections, while the molecular function of this enigmatic gene remains further unresolved.},
  language  = {en}
}
@article{WuZhaoHochreinetal.2023,
  author    = {Wu, Hao and Zhao, Xiufeng and Hochrein, Sophia M. and Eckstein, Miriam and Gubert, Gabriela F. and Kn{\"o}pper, Konrad and Mansilla, Ana Maria and {\"O}ner, Arman and Doucet-Ladev{\`e}ze, Remi and Schmitz, Werner and Ghesqui{\`e}re, Bart and Theurich, Sebastian and Dudek, Jan and Gasteiger, Georg and Zernecke, Alma and Kobold, Sebastian and Kastenm{\"u}ller, Wolfgang and Vaeth, Martin},
  title     = {Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming},
  series = {Nature Communications},
  volume    = {14},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-023-42634-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358052},
  year      = {2023},
  abstract  = {T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.},
  language  = {en}
}