Review Article | Published:

T cell development: better living through chromatin

Nature Immunology volume 8, pages 687694 (2007) | Download Citation

Abstract

T lymphocyte development is directed by a gene-expression program that occurs in the complex nucleoprotein environment of chromatin. This review examines basic principles of chromatin regulation and evaluates ongoing progress toward understanding how the chromatin template is manipulated to control gene expression and gene recombination in developing thymocytes. Special attention is devoted to the loci encoding T cell receptors α and β, T cell coreceptors CD4 and CD8, and the enzyme terminal deoxynucleotidyl transferase. The properties of SATB1, a notable organizer of thymocyte chromatin, are also addressed.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The nucleosome: from genomic organization to genomic regulation. Cell 116, 259–272 (2004).

  2. 2.

    & ATP-dependent chromatin remodeling. Curr. Top. Dev. Biol. 65, 115–148 (2005).

  3. 3.

    The dynamics of chromatin remodeling at promoters. Mol. Cell 19, 147–157 (2005).

  4. 4.

    Nucleosome displacement in transcription. Genes Dev. 20, 2009–2017 (2006).

  5. 5.

    , & The role of chromatin during transcription. Cell 128, 707–719 (2007).

  6. 6.

    & The language of covalent histone modifications. Nature 403, 41–45 (2000).

  7. 7.

    & Heterochromatin: stable and unstable invasions at home and abroad. Genes Dev. 17, 1805–1812 (2003).

  8. 8.

    & Replication of heterochromatin: insights into mechanisms of epigenetic inheritance. Chromosoma 114, 389–402 (2005).

  9. 9.

    , , & Chromatin challenges during DNA replication and repair. Cell 128, 721–733 (2007).

  10. 10.

    Chromatin modifications and their functions. Cell 128, 693–705 (2007).

  11. 11.

    et al. Histone H4–K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).

  12. 12.

    Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243–269 (2006).

  13. 13.

    & Histone H3 Lys 4 methylation: caught in a bind? Genes Dev. 20, 2779–2786 (2006).

  14. 14.

    , & Chromatin remodelling: the industrial revolution of DNA around histones. Nat. Rev. Mol. Cell Biol. 7, 437–447 (2006).

  15. 15.

    et al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282–296 (2006).

  16. 16.

    et al. DNA translocation and loop formation mechanism of chromatin remodeling by SWI/SNF and RSC. Mol. Cell 24, 559–568 (2006).

  17. 17.

    , & Chromatin remodeling by nucleosome disassembly in vitro. Proc. Natl. Acad. Sci. USA 103, 3090–3093 (2006).

  18. 18.

    & de FACTo nucleosome dynamics. J. Biol. Chem. 281, 23297–23301 (2006).

  19. 19.

    & The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 6, 838–849 (2005).

  20. 20.

    & Form follows function: The genomic organization of cellular differentiation. Genes Dev. 18, 1371–1384 (2004).

  21. 21.

    Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007).

  22. 22.

    et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat. Genet. 36, 1065–1071 (2004).

  23. 23.

    et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nat. Genet. 38, 1348–1354 (2006).

  24. 24.

    et al. Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat. Genet. 38, 1005–1014 (2006).

  25. 25.

    et al. The nuclear-envelope protein and transcriptional repressor LAP2β interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation. J. Cell Sci. 118, 4017–4025 (2005).

  26. 26.

    et al. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117, 427–439 (2004).

  27. 27.

    et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296, 158–162 (2002).

  28. 28.

    , , , & The locus control region is required for association of the murine β-globin locus with engaged transcription factories during erythroid maturation. Genes Dev. 20, 1447–1457 (2006).

  29. 29.

    & Gene silencing, cell fate and nuclear organisation. Curr. Opin. Genet. Dev. 12, 193–197 (2002).

  30. 30.

    , , & Accessibility control of V(D)J recombination. Adv. Immunol. 91, 45–109 (2006).

  31. 31.

    , , , & Histone acetylation and hSWI/SNF remodeling act in concert to stimulate V(D)J cleavage of nucleosomal DNA. Mol. Cell 6, 1037–1048 (2000).

  32. 32.

    , & ATP-dependent remodeling by SWI/SNF and ISWI proteins stimulates V(D)J cleavage of 5 S arrays. J. Biol. Chem. 279, 35360–35367 (2004).

  33. 33.

    et al. Targeted inhibition of V(D)J recombination by a histone methyltransferase. Nat. Immunol. 5, 309–316 (2004).

  34. 34.

    , , , & Chromatin remodeling by the T cell receptor (TCR)-β gene enhancer during early T cell development: implications for the control of TCR-β locus recombination. J. Exp. Med. 192, 625–636 (2000).

  35. 35.

    et al. Regulation of TCRβ gene assembly by a promoter/enhancer holocomplex. Immunity 24, 381–391 (2006).

  36. 36.

    et al. Promoter activation by enhancer-dependent and -independent loading of activator and coactivator complexes. Mol. Cell 10, 1479–1487 (2002).

  37. 37.

    , , , & Regulation of V(D)J recombination: A dominant role for promoter positioning in gene segment accessibility. Proc. Natl. Acad. Sci. USA 99, 12309–12314 (2002).

  38. 38.

    et al. The T-cell receptor β variable gene promoter is required for efficient Vβ rearrangement but not allelic exclusion. Mol. Cell. Biol. 24, 7015–7023 (2004).

  39. 39.

    & Turning T-cell receptor β recombination on and off: more questions than answers. Immunol. Rev. 209, 129–141 (2006).

  40. 40.

    et al. Asynchronous replication and allelic exclusion in the immune system. Nature 414, 221–225 (2001).

  41. 41.

    et al. Reversible contraction by looping of the Tcra and Tcrb loci in rearranging thymocytes. Nat. Immunol. 8, 378–387 (2007).

  42. 42.

    , & Germline transcription from T-cell receptor Vβ gene is uncoupled from allelic exclusion. EMBO J. 26, 2387–2399 (2007).

  43. 43.

    , , , & Regulation of T cell receptor β-allelic exclusion at a level beyond accessibility. Nat. Immunol. 6, 189–197 (2005).

  44. 44.

    et al. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 18, 411–422 (2004).

  45. 45.

    , , & Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. Genes Dev. 19, 322–327 (2005).

  46. 46.

    et al. Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat. Immunol. 6, 31–41 (2005).

  47. 47.

    et al. Increase of TCR Vβ accessibility within Eβ regulatory region influences its recombination frequency but not allelic exclusion. J. Immunol. 171, 829–835 (2003).

  48. 48.

    & Allele-specific regulation of TCRβ variable gene segment chromatin structure. J. Immunol. 175, 5186–5191 (2005).

  49. 49.

    & A role for histone acetylation in the developmental regulation of V(D)J recombination. Science 287, 495–498 (2000).

  50. 50.

    & Regulation of TCR δ and α repertoires by local and long-distance control of variable gene segment chromatin structure. J. Exp. Med. 202, 467–472 (2005).

  51. 51.

    , , , & Defect in rearrangement of the most 5′ TCR-Jα following targeted deletion of T early α (TEA): implications for TCRα locus accessibility. Immunity 5, 331–342 (1996).

  52. 52.

    , & Regulation of TCRα gene assembly by a complex hierarchy of germline Jα promoters. Nat. Immunol. 6, 481–489 (2005).

  53. 53.

    & Role for rearranged variable gene segments in directing secondary T cell receptor α recombination. Proc. Natl. Acad. Sci. USA 104, 903–907 (2007).

  54. 54.

    , & de TEA regulates local TCR-Jα accessibility through histone acetylation. Eur. J. Immunol. 33, 2216–2222 (2003).

  55. 55.

    & Regulation of T cell receptor-α gene recombination by transcription. Nat. Immunol. 7, 1109–1115 (2006).

  56. 56.

    et al. Transcription factor Pax5 (BSAP) transactivates the RAG-mediated VH-to-DJH rearrangement of immunoglobulin genes. Nat. Immunol. 7, 616–624 (2006).

  57. 57.

    et al. A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. Immunity 23, 203–212 (2005).

  58. 58.

    et al. A PHD finger motif in the C terminus of RAG2 modulates recombination activity. J. Biol. Chem. 280, 28701–28710 (2005).

  59. 59.

    & A model for TCR gene segment use. J. Immunol. 177, 3857–3864 (2006).

  60. 60.

    & Chromatin in need of a fix: phosphorylation of H2AX connects chromatin to DNA repair. Mol. Cell 18, 617–622 (2005).

  61. 61.

    et al. Response to RAG-mediated VDJ cleavage by NBS1 and γ-H2AX. Science 290, 1962–1965 (2000).

  62. 62.

    , & Phosphorylation of histone H2B at DNA double-strand breaks. J. Exp. Med. 199, 1671–1677 (2004).

  63. 63.

    , & The CD4/CD8 lineage choice: new insights into epigenetic regulation during T cell development. Adv. Immunol. 83, 55–89 (2004).

  64. 64.

    , , & Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Mol. Cell 10, 1083–1096 (2002).

  65. 65.

    et al. Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nat. Genet. 29, 332–336 (2001).

  66. 66.

    et al. Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc. Natl. Acad. Sci. USA 100, 7731–7736 (2003).

  67. 67.

    et al. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity 22, 317–328 (2005).

  68. 68.

    et al. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111, 621–633 (2002).

  69. 69.

    , , , & Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes. J. Immunol. 172, 4359–4370 (2004).

  70. 70.

    et al. RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene 25, 5777–5786 (2006).

  71. 71.

    , , & Runx1 binds positive transcription elongation factor b and represses transcriptional elongation by RNA polymerase II: possible mechanism of CD4 silencing. Mol. Cell. Biol. 25, 10675–10683 (2005).

  72. 72.

    et al. Functional and molecular analysis of the double-positive stage-specific CD8 enhancer E8III during thymocyte development. J. Immunol. 174, 1513–1524 (2005).

  73. 73.

    et al. Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Nat. Immunol. 7, 392–400 (2006).

  74. 74.

    et al. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418, 195–199 (2002).

  75. 75.

    et al. The chromatin remodeler Mi-2β is required for CD4 expression and T cell development. Immunity 20, 719–733 (2004).

  76. 76.

    , , & Dynamic repositioning of CD4 and CD8 genes during T cell development. J. Exp. Med. 200, 1427–1435 (2004).

  77. 77.

    et al. Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice. J. Exp. Med. 200, 1437–1444 (2004).

  78. 78.

    , & Assembly of silent chromatin during thymocyte development. Semin. Immunol. 17, 129–140 (2005).

  79. 79.

    et al. Dynamic assembly of silent chromatin during thymocyte maturation. Nat. Genet. 36, 502–506 (2004).

  80. 80.

    , , , & Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol. Cell 3, 207–217 (1999).

  81. 81.

    Haematopoietic cell-fate decisions, chromatin regulation and Ikaros. Nat. Rev. Immunol. 2, 162–174 (2002).

  82. 82.

    , & Ikaros SUMOylation: switching out of repression. Mol. Cell. Biol. 25, 2688–2697 (2005).

  83. 83.

    et al. Down-regulation of TDT transcription in CD4+CD8+ thymocytes by Ikaros proteins in direct competition with an Ets activator. Genes Dev. 15, 1817–1832 (2001).

  84. 84.

    et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell 91, 845–854 (1997).

  85. 85.

    et al. Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev. 14, 2146–2160 (2000).

  86. 86.

    , & Tissue-specific nuclear architecture and gene expression regulated by SATB1. Nat. Genet. 34, 42–51 (2003).

  87. 87.

    et al. The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple gene during T-cell development. Genes Dev. 14, 521–535 (2000).

  88. 88.

    , , , & SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 419, 641–645 (2002).

  89. 89.

    et al. Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo. Mol. Cell 22, 231–243 (2006).

  90. 90.

    , & SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat. Genet. 38, 1278–1288 (2006).

  91. 91.

    , & Nuclear matrix binding regulates SATB1-mediated transcriptional repression. J. Biol. Chem. 280, 24600–24609 (2005).

  92. 92.

    et al. The CD8α gene locus is regulated by the Ikaros family of proteins. Mol. Cell 10, 1403–1415 (2002).

Download references

Acknowledgements

I thank E. Oltz, Y. Zhuang, B. Sleckman, I. Abarrategui, R. Schlimgen and H. Kondilis for comments on the manuscript, and S. Smale and I. Taniuchi for advice. Supported by the National Institutes of Health (R37 GM41052 and RO1 AI49934).

Author information

Affiliations

  1. Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710 USA.

    • Michael S Krangel

Authors

  1. Search for Michael S Krangel in:

Competing interests

The author declares no competing financial interests.

Corresponding author

Correspondence to Michael S Krangel.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/ni1484

Further reading