T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for ‘self’ are either eliminated through TCR-agonist-induced apoptosis (negative selection)1 or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells3. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs4,5,6. Here we explore in mice whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.
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We thank P. Bos, A. Arvey, C. Konopacki, G. Gasteiger, S. Lee, T. Chinen and K. Wu for technical assistance, CKP IBCH for equipment, and R. Prinjha for providing iBET. Y.F. was supported by a Postdoctoral Fellowship of the Cancer Research Institute. This study was supported by NIH grants R37 AI034206 and U01 HG007893, Cancer Center Support Grant P30 CA008748, and the Howard Hughes Medical Institute (A.Y.R.). M.S., E.V.P. and D.M.C. were supported by MCB program RAS and RFBR grants 14-04-01247 and 15-34-21052.
The authors declare no competing financial interests.
Extended data figures and tables
a, Diminished numbers of thymic Treg cells in 6–8-week-old CNS3-deficient mice. Two-tailed Mann–Whitney test. The data show individual mice and median, and represent 1 of >2 independent experiments. Foxp3gfp (n = 9); Foxp3ΔCNS3-gfp (n = 11). SI, small intestine. b, c, Flow cytometric analysis of CD4 and CD8 SP thymocyte subsets, including thymic Treg precursor (CD4+CD25+Foxp3−) cells (b) and Foxp3 expression (c) in 6–8-week-old Foxp3ΔCNS3-gfp mice (n = 11) and Foxp3gfp (n = 9) littermates. Unpaired Mann–Whitney test. d, e, CNS3-dependent Treg cell differentiation in heterozygous Foxp3CNS3-fl-gfp/+ and Cd4CreFoxp3CNS3-fl-gfp/+ (d), or Foxp3CNS3-fl-gfp/+ and LckCre Foxp3CNS3-fl-gfp/+ females (e). GFP+ and GFP− Treg cells in these mice express Foxp3CNS3-fl-gfp or wild-type Foxp3+ alleles, respectively. The data represent 1 of >2 independent experiments (n ≥ 3 mice per group). f, Acute ablation of CNS3 impairs Treg induction in vitro. Yellow fluorescent protein (YFP)+ (tamoxifen treated) or YFP− (vector control) naive CD4+ T cells from UbcCre-ERT2 Foxp3CNS3-fl-gfp R26Y males were cultured under in vitro Treg induction conditions. The data show mean ± s.e.m. of triplicate cultures and represent 1 of 2 independent experiments. Two-tailed unpaired t-test. g, h, Acute ablation of CNS3 in differentiated Treg cells does not affect Foxp3 expression level on a per cell basis or the stability of mature Treg cells. g, Expression of Foxp3, CD25 and CD44 in Treg cells on day 4 after tamoxifen treatment. h, YFP+ and YFP− Treg cells from tamoxifen-treated UbcCre-ERT2 Foxp3CNS3-fl-gfp R26Y males were cultured in the presence of IL-2, IFNγ, IL-4, IL-6 and IL-12 for 4 days. The data represent 2 independent experiments.
Extended Data Figure 2 CNS3 is dispensable for the suppressor function of differentiated Treg cells in vivo.
a–f, In vivo assessment of the suppressor function of Treg cells upon acute ablation of CNS3. Treg cells (CD4+GFP+) isolated from Foxp3gfp or Foxp3CNS3-fl-gfp mice were activated with CD3 and CD28 antibody-coated beads in vitro for five days and then transduced with retroviruses expressing Cre recombinase and a Thy1.1 reporter. Three days later, Thy1.1+CD4+GFP+ cells were sorted by FACS for the suppressor assay. a, CD4+Foxp3− and CD8+ effector T cells (Teff) sorted from Foxp3DTR reporter mice seven days after diphtheria toxin (DT) injection (1 μg intraperitoneal per mouse) were transferred alone or with equal amounts of Thy1.1+ Cre-transduced Foxp3gfp or Foxp3CNS3-fl-gfp Treg cells into Tcrb−/− Tcrd−/− recipients. b, Mice were weighed before and after T-cell transfer, and relative weight changes were assessed at weeks 3 and 4 post-transfer. c–f, Four weeks after adoptive transfer, cells were recovered and analysed for Treg frequencies and Foxp3 expression (c), CD4+TCRβ+Foxp3− and CD8+TCRβ+ cell numbers (d), IFNγ (e) and IL-13 (f) production. Unpaired Mann–Whitney test (n = 5 per group).
a, b, ChIP–qPCR analysis of H3K4me3 (a) and H3K27ac (b) at the Foxp3 locus and control loci (Hspa2, Rpl30 and Gm5069) in B cells, DP thymocytes, naive CD4+ T and Treg cells. FACS-sorted cells from wild-type male Foxp3DTR mice were used for ChIP–qPCR. Relative enrichment was calculated by normalizing to background binding to control region (Gm5069). c–e, ChIP–qPCR analysis of H3K4me1 (c), H3K4me3 (d) and H3K27ac (e) in the Foxp3 locus in mature Treg cells isolated from wild-type Foxp3gfp and Foxp3ΔCNS3-gfp male mice normalized to the background binding to the Gm5069 locus. f, CNS3-dependent deposition of H3K27ac at the Foxp3 promoter in Foxp3−CD4+ T cells during in vitro Treg cell induction. Foxp3gfp or Foxp3ΔCNS3-gfp naive CD4+ T cells were cultured under in vitro Treg cell differentiation conditions. After three days of culture, GFP− and GFP+ cells were sorted for ChIP–qPCR analysis. Two-tailed unpaired t-test. g, Inhibition of Treg induction in vitro by bromodomain protein inhibitor iBET. Naive CD4+ T cells from wild-type Foxp3gfp males were used for Foxp3 in vitro induction in the presence of indicated concentrations of iBET or vehicle. h, Schematic of the chromatin dynamics at CNS3 and the Foxp3 promoter during Treg cell differentiation. The data are shown as means ± s.e.m. of triplicates and represent 1 of 2 independent experiments.
a, Differential effect of CNS3 on Treg cell in vitro development of mature non-Treg CD4 SP T cells. CD4 SP thymocytes (CD4+CD8−TCRβhiGFP−CD25−CD62LhiCD69lo) were pooled and sorted from male Foxp3gfp and Foxp3ΔCNS3-gfp littermates (n = 7 each group) for in vitro Treg cell induction performed with titrated CD3 antibody and lethally irradiated antigen-presenting cells isolated from wild-type B6 spleens in the presence of TGFβ and recombinant IL-2. Foxp3 expression was analysed four days later and the relative changes in the ratios of Foxp3-expressing cells in the absence of CNS3 were calculated by comparing to CNS3-sufficient groups. Data depict means ± s.e.m. of five replicate cultures and represent 1 of 3 independent experiments. b, Flow cytometric analysis of Nur77 protein expression in CNS3-deficient and -sufficient Treg cells (n = 5 for each group). Two-tailed unpaired Mann–Whitney test. The data represent 1 of >2 independent experiments. c, Increased Nur77 protein levels in CNS3-deficient Treg cells developed after conditional ablation of CNS3 upon tamoxifen-induced activation of UbcCre-ERT2. Bone marrow of CD45.1+ Foxp3gfp and CD45.2+ UbcCre-ERT2 Foxp3CNS3-fl-gfp R26Y mice were collected from donor mice treated with tamoxifen, mixed at a 1:1 ratio and transferred into lethally irradiated Tcrb−/− Tcrd−/− recipients. CD45.1+CD4+GFP+, CD45.2+YFP−GFP+ and CD45.2+YFP+GFP+ cells were sorted for flow cytometric analysis of Nur77 protein levels 10 weeks after bone marrow transfer (n = 5). Unpaired Mann–Whitney tests were used to compare CD45.2+YFP+GFP+ and CD45.2+YFP−GFP+ or CD45.2+YFP+GFP+ and control (CD45.1+CD4+GFP+) groups. The data show medians of individual mice and represent >3 independent experiments. d, Nur77 expression levels in thymic Treg precursors (CD25+Foxp3−), immature (CD62LloCD69hi) and mature (CD62LhiCD69lo) CD4 SP thymocytes, and peripheral Foxp3−CD4+ and CD8+ T cells in 6–7-week-old Foxp3gfp (n = 5) and Foxp3ΔCNS3-gfp (n = 4) littermates. Unpaired Mann–Whitney test. The data show medians of individual mice and represent >3 independent experiments. e, Differential Nur77 expression in peripheral resting (CD44loCD62Lhi) and activated (CD44hiCD62Llo) Treg cells (wild-type Foxp3gfp). The data represent 1 of >3 independent experiments. f, g, Upregulation of Nur77 expression in resting (CD44loCD62Lhi) (f) and activated (CD44hiCD62Llo) (g) CNS3-deficient Treg cells in 6–7-week-old Foxp3gfp (n = 5) and Foxp3ΔCNS3-gfp (n = 4) littermates. Unpaired Mann–Whitney test. The data represent >3 experiments. h, i, CTLA4 (h) and Ki-67 (i) expression by CNS3-deficient and -sufficient Treg cells in Foxp3gfp (n = 9) and Foxp3ΔCNS3-gfp (n = 11) mice (h). Foxp3gfp (n = 5); Foxp3ΔCNS3-gfp (n = 4) (i). Two-tailed unpaired Mann–Whitney test. The data represent 1 of >3 independent experiments.
a, Principal component analysis of mRNA expression in CNS3-deficient and -sufficient mature Foxp3− and Foxp3+ CD4 SP thymocytes, and peripheral resting and activated Treg cells. RNA-seq was performed with three and four biological replicates for cells sorted from male Foxp3gfp and Foxp3ΔCNS3-gfp littermates, respectively. Dots represent samples from individual mice. b, c, Relative gene expression levels (cumulative fraction of genes) in CNS3-sufficient and -deficient peripheral resting (b) or activated (c) Treg cells in comparison to those up- and downregulated in activated versus resting Treg cells isolated from Foxp3gfp mice. The numbers of genes in each comparison group are indicated in parentheses. d, e, Relative gene expression levels in CNS3-sufficient and -deficient peripheral rTreg (d) or aTreg (e) cells in comparison to those downregulated in activated Treg cells subjected to acute TCR ablation versus mock treatment. The numbers of genes in each comparison group are indicated in parentheses. One-tailed Kolmogorov–Smirnov test. f, Flow cytometric analysis of Foxp3 expression level (median fluorescence intensity (MFI)) in CNS3-sufficient and -deficient Treg cells after expansion in lymphopenic recipients. Treg cells were sorted from mixed bone marrow chimaeras of CD45.1+ Foxp3gfp and CD45.2+ Foxp3ΔCNS3-gfp mice and mixed at a 1:1 ratio, and co-transferred with wild-type naive Foxp3−CD4+ T cells into Tcrb−/− Tcrd−/− recipients treated with MHC-II-blocking antibody or isotype-control IgG before and after the transfer (n = 5 per group). Mean ± s.e.m; the data represent 1 of 3 independent experiments. Unpaired t-test revealed no statistically significant difference between matched CNS3-deficient and -sufficient groups (P > 0.3). g, Comparison of CNS3-sufficient and -deficient Treg cells in competitive environment of heterozygous Foxp3gfp/+ and Foxp3ΔCNS3-gfp/+ females (6–8 weeks of age). In contrast to CNS3-sufficient Treg cells, CNS3-deficient cells are relatively enriched in the periphery in comparison with the thymus. Ratios of GFP− to GFP+ Treg cells are inversely proportional to the relative abundance of Foxp3gfp or Foxp3ΔCNS3-gfp Treg cells in the Treg pool. Wilcoxon matched-pairs signed rank test; Foxp3gfp/+ (n = 5), Foxp3ΔCNS3-gfp/+ (n = 8). Linked circles represent samples from the same mice. Data represent 1 of 2 independent experiments. h, i, Numbers of strongly interacting amino acid residues (LFIMVWCY) were calculated for the V-segment of TCRα CDR3 (binned to germline) and V–J segment junction, and weighted by the corresponding clonotype frequencies. Sums of the weighted scores were used for the comparisons between CNS3-deficient and -sufficient groups (unpaired t-test). The data represent the analysis of pooled TCR sequences derived from the indicated thymic (h) and peripheral (i) CD4+ naive (Tn), activated effector (Teff) and Treg cell subsets isolated from individual Foxp3gfp (n = 5) and Foxp3ΔCNS3-gfp (n = 3) mice. Box-and-whisker plots show minimum, maximum, first and third quartiles and median.
a, CNS3 deficiency does not affect antibody production against a subset of autoantigens. Foxp3ΔCNS3-gfp and Foxp3gfp littermates (n = 4 per group). Box-and-whisker plots show minimum, maximum, first and third quartiles and median. Data represent 1 of 2 independent experiments. b–f, CNS3 deficiency decreases experimental autoimmune encephalomyelitis severity. On immunization with MOG peptide in CFA, mice of indicated genotypes were assessed for the severity of limb paralysis (b), effector T-cell numbers (c), Treg cell frequency (d), Foxp3 expression levels (e) and inflammatory cytokine production (f). Foxp3gfp (n = 8); Foxp3ΔCNS3-gfp (n = 11). Unpaired t-test (b) or Mann–Whitney test (c–f). Mean and s.e.m. are presented (b). *P < 0.05, **P < 0.01. The data represent 2 independent experiments. g, h, Analysis of the proportion of Treg cells in CD4+TCRβ+ cell population (g) and level of Foxp3 expression (MFI) (h) in an in vivo suppressor assay of CNS3-deficient or -sufficient Treg cells (Fig. 3e–h). Two-tailed unpaired Mann–Whitney test.
a, Autoimmune diseases in Foxp3ΔCNS3-gfp AireKO/KO (DKO) mice. Arrow indicates the inflammatory lesions in the tail of a 3-week-old mouse with an early onset of autoimmunity (n >11) (i). De-pigmentation in a 6-week-old mouse with delayed onset of autoimmunity (n > 16) (ii). b, Analysis of serum Ig isotypes in Foxp3ΔCNS3-gfp AireKO/KO and littermate control mice using ELISA (n = 8 per group). Error bars, mean ± s.e.m. Two-way ANOVA. c, Flow cytometric analysis of Foxp3 expression by Treg cells. The data show one of at least three mice per group and represent >3 independent experiments. d–i, Analysis of the ability of CNS3-deficient and -sufficient Treg cells to control CNS3 Aire DKO effector T cells on adoptive transfer into T-cell-deficient recipients. Flow cytometric analysis of non-Treg CD4+ T-cell numbers (d), Treg cell numbers (e), Foxp3 expression levels (f), IFNγ production (g), IL-17 production (h), and serum IgG1 and IgG2b levels (i) in recipient mice transferred with CNS3 and Aire DKO effector T cells (Foxp3−CD4+ and CD8+) at a 10:1 ratio with Treg cells from Aire-sufficient Foxp3gfp or Foxp3ΔCNS3-gfp mice. Two-tailed unpaired Mann–Whitney tests (d–h) or unpaired t-test (i). Error bars, mean ± s.e.m. (i). The recipient mice were analysed 7 weeks after adoptive T-cell transfer (n = 5 per group).
a, Hypothetical distribution of TCRs expressed by Treg and non-Treg CD4+ T cells according to their affinities for self-antigens. Precursor cells expressing TCRs within a certain low-affinity window are positively selected and become ‘conventional’ CD4+ T cells, and those with higher affinities for self-antigens differentiate into Treg cells. CNS3 promotes the differentiation of Treg cells and broadens their TCR repertoire by facilitating Foxp3 expression predominantly in response to lower strength (‘suboptimal’) inducing TCR signals. b, After expansion in the periphery, CNS3-deficient Treg cells reach similar numbers as their wild-type counterparts, with some TCRs underrepresented (A), some minimally affected (B), and some overrepresented (C). Tconv, conventional T cells.
The file shows the numbers of added nucleotides in TCRα CDR3 . (PDF 65 kb)
This file shows up‐regulated genes in activated vs resting Treg cells. (PDF 557 kb)
This files shows down‐regulated genes in activated vs resting Treg cells. (PDF 424 kb)
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Feng, Y., van der Veeken, J., Shugay, M. et al. A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance. Nature 528, 132–136 (2015). https://doi.org/10.1038/nature16141
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