Fig. 4: SIRT2 deficiency alters T cell development and exacerbates ConA-induced autoimmune activation.

a, Ratio of donor-derived WT CD45.1⁺ and Sirt2^−/− CD45.2⁺ DN1–DN4, DP, CD4⁺ SP and CD8⁺ SP thymocytes in the thymus of lethally irradiated C57BL/6×C57BL/6.SJL F1 recipient analyzed 8 weeks after reconstitution with a 1:1 mixture of WT and Sirt2^−/− whole BM cells normalized to the input of WT versus Sirt2^−/− Sca-1⁺ c-kit⁺ HSCs in the BM of the same recipient mice at 8 weeks post-reconstitution. Each dot represents one mouse (n = 4 recipient mice). b, Ratio of WT CD45.1⁺ versus Sirt2^−/− CD45.1⁺ CD4⁺ and CD8⁺ T cells in the spleen and LN recipient mice as in a at 8 weeks post-reconstitution, normalized to the WT versus Sirt2^−/− HSC input in the BM of the same recipient mice at 8 weeks post-reconstitution (n = 4 recipient mice). c, Frequency of WT CD45.1⁺ versus Sirt2^−/− CD45.2⁺ Sca-1⁺ c-kit⁺ HSC at 8 weeks post-reconstitution in the BM of recipient mice as in a (n = 4 recipient mice). d, Ratio of DN3, DN4, DP, CD4⁺ SP and CD8⁺ SP thymocytes in the thymus of recipient mice as in a at 8 weeks post-reconstitution normalized to the number of WT versus Sirt2^−/− DN3 thymocytes. e,f, Frequency of productive TCRβ rearrangements (e) and TCR clonality index (f) in CD8⁺ SP thymocytes from WT and Sirt2^−/− mice determined by TCR deep sequencing (n = 6 mice per group). g, Representative flow cytometry analysis of TCRβ⁺ cells in the spleen of Rag2^−/− mice 24 h after adoptive transfer of vehicle or CD3⁺ T cells from WT or Sirt2^−/− donor mice (n = 5 mice per group). h, Survival of Rag2^−/− mice injected i.v. with 15 mg kg⁻¹ body weight ConA 24 h after adoptive transfer of vehicle, WT or Sirt2^−/− CD3⁺ T cells, assessed 12 h after ConA injection. Vehicle, n = 9 mice; WT, n = 12 mice; and Sirt2^−/−, n = 14 mice. i, Representative H&E staining of liver sections from Rag2^−/− mice adoptively transferred with vehicle, WT CD3⁺ T cells and Sirt2^−/− CD3⁺ T cells as in h at 24 h after ConA injection. Areas of necrosis are circled. Scale bar, 700 µm. j, Quantification of liver damage area, serum ALT and serum AST at 24 h after ConA injection in Rag2^−/− mice adoptively transferred with vehicle, WT CD3⁺ T cells and Sirt2^−/− CD3⁺ T cells as in h. n = 5 mice per group. Data are shown as mean ± s.e.m. Statistical analysis was performed using two-way ANOVA (a,b,d), two-tailed Student’s t-test (c), two-sided Dunn’s test (e,f), two-sided Fisher’s exact test (h) and one-way ANOVA (j). Data are representative of two (f–n) and four (a) independent experiments.

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