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Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance

Abstract

T cell homeostasis is crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatory T cells or an inability to shut down immune responses can lead to inflammation and autoimmune pathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of terminal B cell differentiation, was expressed in a subset of antigen-experienced CD4+ and CD8+ T cells. Mice reconstituted with fetal liver stem cells expressing a mutant Blimp-1 lacking the DNA-binding domain developed a lethal multiorgan inflammatory disease caused by an accumulation of effector and memory T cells. These data identify Blimp-1 as an essential regulator of T cell homeostasis and suggest that Blimp-1 regulates both B cell and T cell differentiation.

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Acknowledgements

We thank J. Carneli, K. D'Costa, L. Di Rago and J. Brady for assistance; D. Huang, G. Davey, Y. Zhan, J. Dromey, W. Heath, D. Tarlinton and A. Strasser for reagents, advice and critical reading of the manuscript; and S. Read (Bio21 Molecular Science and Biotechnology Institute, Melbourne, Victoria, Australia) for help in setting up and analyzing the colitis model. Supported by The Walter and Eliza Hall Institute (Metcalf Fellowship to S.L.N.), the Deutsche Forschungsgemeinschaft (A.K. and M.H.), the Leukaemia Foundation of Australia (A.K.), the National Institutes of Health (CA22556 to D.M.), the Wellcome Trust (G.T.B.), Howard Hughes International Fellowship (G.T.B.) and the National Health and Medical Research Council of Australia.

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Competing interests

The authors declare no competing financial interests.

Correspondence to Stephen L Nutt.

Supplementary information

Supplementary Fig. 1

Blimp-1 controls the number of effector and memory CD4+ T cells. (PDF 831 kb)

Supplementary Methods (PDF 12 kb)

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Figure 1: Blimp-1-deficient mice develop a lethal lymphocyte hyperproliferative syndrome.
Figure 2: Blimp-1 is expressed in and controls the number of effector and memory CD4+ T cells.
Figure 3: Blimp-1 is expressed in and controls the number of effector and memory CD8+ T cells.
Figure 4: Blimp-1 intrinsically regulates the homeostatic population expansion of T cells.
Figure 5: Blimp-1 is dispensable for Treg cell function.
Figure 6: Blimp-1 expression in vitro.
Figure 7: Blimp-1 regulates T cell numbers in vitro.
Figure 8: Blimp-1-mutant T cells are less susceptible than wild-type cells to apoptosis.