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The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes

Abstract

The CD4 versus CD8 lineage specification of thymocytes is linked to coreceptor expression. The transcription factor MAZR has been identified as an important regulator of Cd8 expression. Here we show that variegated CD8 expression by loss of Cd8 enhancers was reverted in MAZR-deficient mice, which confirms that MAZR negatively regulates the Cd8 loci during the transition to the double-positive (DP) stage. Moreover, loss of MAZR led to partial redirection of major histocompatibility complex (MHC) class I–restricted thymocytes into CD4+ helper-like T cells, which correlated with derepression of Th-POK, a central transcription factor for helper-lineage development. MAZR bound the silencer of the gene encoding Th-POK, which indicated direct regulation of this locus by MAZR. Thus, MAZR is part of the transcription factor network that regulates the CD8 lineage differentiation of DP thymocytes.

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Figure 1: Altered ratio of CD4+ T cells to CD8+ T cells in the absence of MAZR.
Figure 2: Less variegation of CD8 in mice doubly deficient in E8I and E8II in the absence of MAZR.
Figure 3: T cell–intrinsic defects lead to an altered ratio of CD4+ cells to CD8+ cells in Mazr−/− mice.
Figure 4: T cell development in MHC class I– and class II–restricted TCR-transgenic mice in the absence of MAZR.
Figure 5: Redirected differentiation of MHC class I–restricted thymocytes into helper lineage cells in the absence of MAZR.
Figure 6: Derepression of Th-POK in Mazr−/−Rag2−/− OT-I thymocytes and CD8+ T cells.
Figure 7: Derepression of Th-POK in MHC class I–signaled Mazr−/− thymocytes.

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Acknowledgements

We thank M. Sibilia (Medical University of Vienna) for OT-I TCR-transgenic mice; D. Stoiber-Sakaguchi (Medical University of Vienna) for OT-II TCR-transgenic mice; W. Held (Glaxo) for recombinant human interleukin 2; J. Kaye for information about primer sequences that detect Tox expression; M. Willheim and G. Hofbauer for cell sorting; H. Tanaka for technical advice; E. Pfeiffer for help with irradiation; M. Busslinger for help with some animal experiments; D. Stoiber-Sakaguchi, J. Raberger and N. Boucheron for critical reading of the manuscript; and the National Institutes of Health Tetramer facility for CD1d reagents with and without PBS57. Supported by the Austrian Science Fund (P16708 and P19930), the START Program of the Austrian Ministry of Science and Research (project Y-163), the RIKEN Research Center for Allergy and Immunology (International Collaboration Program) and the Ernst Schering Foundation (M.H.).

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S.S. designed the research, did most of the experiments, analyzed the data and wrote the manuscript; M.H. did coimmunoprecipitation and ChIP assays; A.S. and Y.N. did ChIP assays; I.B. contributed to the generation of Mazr-deficient mice and did some of the bone marrow–transplantation experiments; I.T. provided reagents and experimental mice and contributed to the design of the research; and W.E. designed the research, contributed to the generation of Mazr-deficient mice, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Wilfried Ellmeier.

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The authors declare no competing financial interests.

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Supplementary Figures 1–11 and Supplementary Table 1 (PDF 3065 kb)

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Sakaguchi, S., Hombauer, M., Bilic, I. et al. The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes. Nat Immunol 11, 442–448 (2010). https://doi.org/10.1038/ni.1860

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