- Author
-
F.M. Behr
- Title
- To settle or wander
- Subtitle
- Transcriptional regulation and recall responses of tissue-resident memory T cells
- Supervisors
-
R.A.W. van Lier
- Co-supervisors
-
K.P.J.M. van Gisbergen
- Award date
- 9 October 2020
- Number of pages
- 327
- ISBN
- 9789464190021
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Tissue-resident memory CD8+T (TRM) cells localize to barrier tissues, where they mediate efficient local protection against reinvading pathogens. TRM cells are thus crucial for tissue immunity, but many aspects of TRM cell biology, including the transcription factors regulating TRM development and their fate following reinfection, have remained incompletely understood. In this thesis, we have studied the transcriptional program governing tissue residency and the secondary responses of TRM cells. Our research highlights the transcription factors Hobit and Blimp-1 as central drivers of TRM formation through the suppression of tissue-egress pathways. Hobit is expressed by TRM cells throughout tissues and identifies early commitment to the TRM lineage. Hobit and Blimp-1 further contribute to TRM cell identity by controlling the maintenance of cytotoxic effector functions. In contrast, the transcription factor Eomes regulates TRM cell differentiation by restricting the formation of TRM precursors and favoring TCM development. Following reinfection, pathogen-specific TRM cells contribute substantially to local and systemic CD8+ T cell responses, and give rise to a functionally distinct subset of secondary circulating memory CD8+ T cells. However, following inflammation in the absence of antigen, the maintenance of non-specific TRM populations is regulated by local tissue damage. Circulating memory CD8+ T cells only minimally contribute to secondary effector and memory responses at mucosal sites after reinfection. Taken together, our findings provide important insights into the mechanisms controlling the formation, maintenance, and secondary responses of TRM cells, which may be exploited to harness the superior protective capacity of TRM cells for future therapeutic approaches.
- Persistent Identifier
- https://hdl.handle.net/11245.1/fb00439a-5b4d-4e98-a273-bc6636c74ff0
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytes
Chapter 3: Blimp-1 rather than Hobit drives the formation of tissue- resident memory CD8⁺ T cells in the lungs
Chapter 4: Blimp‐1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells
Chapter 5: Eomes regulates early establishment of the Hobit⁺ Tʀм lineage
Chapter 6: Hobit identifies tissue-resident memory CD4⁺ T cell development after viral and bacterial infection
Chapter 7: Tʀм maintenance is regulated by tissue damage via P2RX7
Chapter 8: Tissue-resident memory CD8⁺ T cells shape local and systemic secondary T cell responses
Chapter 9: Limited contribution of circulating memory CD8⁺ T cells to resident memory at mucosal sites after reinfection
Chapter 10: General discussion
English summary; Nederlandse samenvatting; Deutsche Zusammenfassung; PhD portfolio; Curriculum vitae; List of publications; Acknowledgements
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