Regulatory T cells (Treg cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in Treg cell development. Mice that lacked all Nr4a factors could not produce Treg cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the Treg cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4+ T cell fates in the thymus and thus contribute to immune homeostasis.
At a glance
- Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30, 95–114 (2012). , &
- Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003). , &
- Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003). , &
- An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003). , , &
- The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001). et al.
- Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).
- Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000).
- Development of Foxp3+ regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31, 932–940 (2009). et al.
- Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921–931 (2009). , , , &
- Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010). et al.
- Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202 (2008). et al.
- IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006). et al.
- Indispensable role of the Runx1-Cbfβ transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells. Immunity 31, 609–620 (2009). et al.
- Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 10, 1170–1177 (2009). et al.
- Runx proteins regulate Foxp3 expression. J. Exp. Med. 206, 2329–2337 (2009). et al.
- Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat. Immunol. 11, 618–627 (2010). et al.
- The Ets-1 transcription factor controls the development and function of natural regulatory T cells. J. Exp. Med. 207, 2113–2125 (2010). et al.
- Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003). et al.
- Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423, 555–560 (2003). et al.
- Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J. 16, 1865–1875 (1997). , , &
- The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nat. Commun. 2, 269 (2011). et al.
- T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011). et al.
- Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007). et al.
- Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009). et al.
- Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8, 359–368 (2007). et al.
- Transcriptional analysis of clonal deletion in vivo. J. Immunol. 179, 837–844 (2007). &
- Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Proc. Natl. Acad. Sci. USA 109, 3891–3896 (2012). , , , &
- Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J. Exp. Med. 183, 1879–1892 (1996). et al.
- A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3, 273–282 (1995). , , , &
- The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome. Proc. Natl. Acad. Sci. USA 87, 2433–2437 (1990). , , , &
- X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379–1387 (1991). , &
- Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009). &
- Targeted expression of major histocompatibility complex (MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo. J. Exp. Med. 185, 541–550 (1997). , &
- Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules. J. Exp. Med. 186, 1269–1275 (1997). , &
- Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat. Med. 13, 730–735 (2007). et al.
- A two-step process for thymic regulatory T cell development. Immunity 28, 100–111 (2008). &
- Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. USA 105, 19869–19874 (2008). et al.
- The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat. Cell Biol. 12, 1213–1219 (2010). , , , &
- Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. J. Biol. Chem. 276, 32799–32805 (2001). et al.
- Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes. Eur. J. Immunol. 26, 161–165 (1996). et al.
- Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice. J. Immunol. 183, 5662–5672 (2009). et al.
- How are TH2-type immune responses initiated and amplified? Nat. Rev. Immunol. 10, 225–235 (2010). &
- Nur77 transcription activity correlates with its apoptotic function in vivo. Eur. J. Immunol. 29, 3722–3728 (1999). , &
- LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J. Exp. Med. 203, 119–129 (2006). , , &
- The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat. Immunol. 7, 851–858 (2006). , , , &
- Differential requirement for CARMA1 in agonist-selected T-cell development. Eur. J. Immunol. 39, 78–84 (2009). et al.
- Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proc. Natl. Acad. Sci. USA 101, 4566–4571 (2004). et al.
- Mature T cells depend on signaling through the IKK complex. Immunity 19, 377–389 (2003). et al.
- Differential requirement of PKC-θ in the development and function of natural regulatory T cells. Mol. Immunol. 46, 213–224 (2008). et al.
- Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J. Neurosci. 29, 15923–15932 (2009). et al.
- Supplementary Text and Figures (606K)
Supplementary Figures 1–6