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iNKT cells promote tolerance by cDC apoptosis
diversity of iNKT cells we assume that several mecha- nisms, that are not mutually exclusive, are generally involved in tolerance induction: modulation of DC func- tion, expansion of FoxP3 regulatory T cells, induction of a Th2 bias of T-helper cells and decreased expansion of alloreactive donor T cells. Indeed, it has been observed that distinct iNKT-cell subsets are associated with certain functional properties which might explain different find- ings from other groups in humans and mice. Also, culture conditions might affect the function of iNKT cells after expansion.
In conclusion, we postulate an additional mechanism by which iNKT cells prevent GvHD in humans, focusing on their interaction with different DC subsets. iNKT cells promote selective cDC apoptosis through the release of effector molecules such as perforin and granzyme B in a cell-contact-dependent manner, which could consequent- ly prevent GvHD. However, pDC are spared and may still convey beneficial immune responses leading to efficient GvL effects and pathogen control resulting in improved survival after allogenic HCT.
Disclosures
No conflicts of interest to disclose
Contributions
HS, EMR and DS designed and performed the research and analyzed data; K-AS SD-S, HK, RD, TM, KS-O, SH and
CS performed the research and analyzed data; EMR and DS wrote the manuscript. All authors edited the manuscript for con- tent.
Acknowledgments
We would like to thank the Flow Cytometry Core Facility of the University Hospital Tuebingen for their excellent technical sup- port. Furthermore, we thank Stella Autenrieth for sharing her expertise about dendritic cell biology and Kirsten Lauber for many fruitful discussions about apoptosis.
Funding
This study was supported by a Max Eder Research fellowship of the German Cancer Aid (Deutsche Krebshilfe, 70112548), a Junior Research Group Grant of the Interdisciplinary Center for Clinical Research (IZKF, 2316-0-0) and the Clinician Scientist Program of the Faculty of Medicine Tuebingen. HS received a grant from the Ludwig Hiermaier Foundation. CS was funded by a Junior Research Group Grant of the Interdisciplinary Center for Clinical Research (IZKF, 2383-0-0), the Clinician Scientist Program of the Faculty of Medicine Tuebingen and the Wuerttemberg Cancer Award (Wuerttembergischer Krebspreis). The National Institutes of Health Tetramer Core Facility kindly provided CD1d tetramer reagents.
Data sharing statement
Raw data and detailed protocols of the used methods used can be obtained upon direct request to the corresponding author.
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