Abstract
Stra13, a basic helix-loop-helix transcription factor, is up-regulated upon activation of CD4+ T cells. Here we show that Stra13-deficient mice exhibit defects in several phases of CD4+ T cell activation. In vivo, Stra13 deficiency results in ineffective elimination of activated T and B cells, which accumulate progressively, leading to lymphoid organ hyperplasia. Consequently, aging Stra13−/− mice develop autoimmune disease characterized by accumulation of spontaneously activated T and B cells, circulating autoantibodies, infiltration of T and B lymphocytes in several organs and immune complex deposition in glomeruli. Our studies identify Stra13 as a key regulator of lymphocyte activation that is vital for maintenance of self-tolerance and for constraint of autoimmunity.
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Acknowledgements
We thank G. Cattoretti for advice on histopathology, M. Mendelsohn for blastocyst injections, P. Chambon for Stra13 antibodies and E. Eynon and D. Hesslein for advice and reagents. We are grateful to K. Calame, G. Cattoretti and J. Bieker for comments on the manuscript. B.L. is an Associate and R.A.F. is an Investigator of the Howard Hughes Medical Institute. R.T. is a Basil O'Connor Research Scholar. Supported in part by grants from the NIH, March of Dimes, Waxman Cancer Research Foundation and Charlotte Geyer Foundation (to R.T.).
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Web Figure 1.
Flow cytometric analysis of thymocytes from 8-week old wild-type and Stra13-deficient mice. Thymocytes were stained with various cell surface markers as indicated. (GIF 61 kb)
Web Figure 2.
Flow cytometric analysis of bone marrow cells from 8-week-old wild-type and Stra13-deficient mice. Cells were stained with lineage specific markers as indicated. (GIF 66 kb)
Web Figure 3.
KLH-specific primary antibody responses. Wild-type (filled circle) and Stra13-/- (open circle) mice were immunized with KLH in CFA, and bled on day 14 after boosting. KLH-specific Ig was analyzed by ELISA. (GIF 25 kb)
Web Figure 4.
Analysis of B cell clonality by PCR. DNA samples prepared from spleen of 8-month old wild-type (+/+) and Stra13-/- mice were analyzed for DH-JH rearrangement. The predicted rearrangements using various J segments are shown. The expected size of JH1, JH2 and JH3 are 1.2, 0.7 and 0.3-0.4 kb. (GIF 40 kb)
Web Figure 5.
Analysis of B1 B cells in 8-month old wild-type and Stra13-deficient mice. Single cell suspension from spleen and peritoneum were double-stained with anti-IgM and anti-CD5 and analyzed by flow cytometric analysis. (GIF 58 kb)
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Sun, H., Lu, B., Li, RQ. et al. Defective T cell activation and autoimmune disorder in Stra13-deficient mice. Nat Immunol 2, 1040–1047 (2001). https://doi.org/10.1038/ni721
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DOI: https://doi.org/10.1038/ni721
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