期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.535039
关键词
MAZR; PATZ1; Runx3; cytotoxic T lymphocyte; transcriptional control; LCMV; memory T cell
类别
资金
- Austrian Science Fund (FWF) [P23669, P27747, P29790, P23991, P25360, P30047]
- L'OREAL Austria Fellowship Programm by L'OREAL Austria
- Austrian UNESCO Commission
- Austrian Academy of Sciences
- Federal Ministry of Education, Science and Research
- Medical University of Vienna doctoral programs [DK W1212, DOC 32]
- ERC Starting Grant (European Union's Horizon 2020 research and innovation program) [677006]
- DOC Fellowship Programme of the Austrian Academy of Sciences
- European Union's Horizon 2020 research and innovation programme ENLIGHT-TEN under the Marie Sklodowska-Curie grant [675395]
- European Research Council ERC [677943]
- European Union's Horizon 2020 research and innovation programme [675395]
- Academy of Finland [296801, 304995, 310561, 313343]
- Juvenile Diabetes Research Foundation JDRF [2-2013-32]
- Tekes - the Finnish Funding Agency for Innovation [1877/31/2016]
- Sigrid Juselius Foundation
- Turku Graduate School (UTUGS), University of Turku
- Abo Akademi University
- Biocenter Finland
- ELIXIR Finland node
- Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health
- Austrian Science Fund (FWF) [P27747, P23669, P23991, P25360, P30047, P29790] Funding Source: Austrian Science Fund (FWF)
The transcription factor MAZR partially compensates for the loss of Runx3 in CTLs, as demonstrated through transcriptome analysis. MAZR and Runx3 cooperatively regulate the expression of key genes in CTLs, while showing distinct functions in the differentiation of memory T cell subsets. This study provides insights into the complex interplay between MAZR and Runx3 in the development of CTL and memory T cell pools.
The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8(+) T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs in vitro. However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made in vitro, the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8 alpha, Granzyme B and perforin in vivo. Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools.
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