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Research Newsletter - September 2007

Spotlight

In an article paper published in The Journal of Experimental Medicine, HSCI Faculty Executive Committee member Diane Mathis, and HSCI Affiliated Faculty member Christophe Benoist, both of the Joslin Diabetes Center, report findings regarding the lineage relationship between conventional and regulatory T cells.

TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets

Regulatory T cells are critical controllers of immune responses against self-proteins (autoimmunity), allergens, microbes and tumors. The best-characterized class, affectionately called Tregs, is marked by expression of the transcription factor, FoxP3. Current thinking holds that there are two types of FoxP3+ regulatory T cells: those produced constitutively in the thymus, termed natural Tregs, and those generated de novo during certain immune responses through conversion of the T cells actually engaged in the response, called T conventional cells. The lineage relationship between these two types of Tregs, and between them and T conventional cells is not known. This paper from the Benoist and Mathis lab uses the sequence of the antigen-specific receptor every T cell displays (T cell receptor or TCR) as a lineage tag to address to what extent T conventional cells convert to Tregs during an autoimmune response to a diabetogenic autoantigen expressed by pancreatic islet beta cells. Using single-cell sequencing of sorted Treg and T conventional cells from the pancreas and various lymphoid organs, they found no evidence of the latter converting into the former. It is important to understand just how Tregs can be generated, particularly during an autoimmune response, because of the current interest in infusing them for therapeutic purposes.

Wong J, Mathis D, Benoist C. TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets. J Exp Med. 2007 Sep 3;204(9):2039-45. Read abstract.

Scientific Papers

Review and Commentary

  • Agarwal S, Lensch MW, Daley GQ. Current prospects for the generation of patient-specific pluripotent cells from adult tissues. Regen Med. 2007 Sep;2(5):743-52. Read Abstract.
  • Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol. 2007 Oct 8. Read Abstract.
  • Hochedlinger K. Konrad Hochedlinger: the new kid of nuclear reprogramming. J Cell Biol. 2007 Sep 24;178(7):1098-9. Read Abstract.
  • Lensch MW, Schlaeger TM, Zon LI, and Daley GQ. Teratoma Formation Assays with Human Embryonic Stem Cells: A Rationale for One Type of Human-Animal Chimera Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract.
  • Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007 Sep;7(9):673-83. Review. Read Abstract.
  • Orkin SH, and Pera M. Stem Cells Down Under - ISSCR 2007 Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract.
  • Purton LE, and Scadden DT. Limiting Factors in Murine Hematopoietic Stem Cell Assays Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract.
  • Xie H, Orkin SH. Immunology: changed destiny. Nature. 2007 Sep 27;449(7161):410-1. Read Abstract.

Blood

  • Barry EV, Clark JJ, Cools J, Roesel J, Gilliland DG. Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin. Blood. 2007 Sep 7. Read Abstract.
  • Hoogenkamp M, Krysinska H, Ingram R, Huang G, Barlow R, Clarke D, Ebralidze A, Zhang P, Tagoh H, Cockerill PN, Tenen DG, Bonifer C. The pu.1 locus is differentially regulated at the level of chromatin structure and noncoding transcription by alternate mechanisms at distinct developmental stages of hematopoiesis. Mol Cell Biol. 2007 Nov;27(21):7425-38. Epub 2007 Sep 4. Read Abstract.
  • Steidl U, Steidl C, Ebralidze A, Chapuy B, Han HJ, Will B, Rosenbauer F, Becker A, Wagner K, Koschmieder S, Kobayashi S, Costa DB, Schulz T, O'Brien KB, Verhaak RG, Delwel R, Haase D, Trumper L, Krauter J, Kohwi-Shigematsu T, Griesinger F, Tenen DG. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J Clin Invest. 2007 Sep;117(9):2611-20. Read Abstract.
  • Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J, Kung AL, Armstrong SA. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia. 2007 Sep 13. Read Abstract.

Cancer

  • Cortes J, Jabbour E, Daley GQ, O'Brien S, Verstovsek S, Ferrajoli A, Koller C, Zhu Y, Statkevich P, Kantarjian H. Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer. 2007 Sep 15;110(6):1295-302. Read Abstract.
  • Faber J, Armstrong SA. Mixed lineage leukemia translocations and a leukemia stem cell program. Cancer Res. 2007 Sep 15;67(18):8425-8. Read Abstract.
  • Kang S, Dong S, Gu TL, Guo A, Cohen MS, Lonial S, Khoury HJ, Fabbro D, Gilliland DG, Bergsagel PL, Taunton J, Polakiewicz RD, Chen J. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. Cancer Cell. 2007 Sep;12(3):201-14. Read Abstract.

Cardiovascular System

  • Karkera JD, Lee JS, Roessler E, Banerjee-Basu S, Ouspenskaia MV, Mez J, Goldmuntz E, Bowers P, Towbin J, Belmont JW, Baxevanis AD, Schier AF, Muenke M. Loss-of-Function Mutations in Growth Differentiation Factor-1 (GDF1) Are Associated with Congenital Heart Defects in Humans. Am J Hum Genet. 2007 Nov;81(5):987-94. Epub 2007 Sep 28. Read Abstract.
  • Zhao Y, Lim CC, Sawyer DB, Liao R, Zhang X. Simultaneous orientation and cellular force measurements in adult cardiac myocytes using three-dimensional polymeric microstructures. Cell Motil Cytoskeleton. 2007 Sep;64(9):718-25. Read Abstract.

Cell Biology

  • Kim K, Ng K, Rugg-Gunn PJ, Shieh JH, Kirak O, Jaenisch R, Wakayama T, Moore MA, Pedersen RA, and Daley GQ. Recombination Signatures Distinguish Embryonic Stem Cells Derived by Parthenogenesis and Somatic Cell Nuclear Transfer Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract.
  • Shibolet O, Giallourakis C, Rosenberg I, Mueller T, Xavier RJ, Podolsky DK. AKAP13 a rhoa GTPase-specific guanine exchange factor is a novel regulator of TLR2 signaling. J Biol Chem. 2007 Sep 18. Read Abstract.
  • Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007 Sep 21;130(6):1095-107. Read Abstract.

Developmental Biology

  • Aidlen JT, Nazarey PP, Kinane TB, Donahoe PK, Schnitzer JJ, Kling DE. Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis. Birth Defects Res B Dev Reprod Toxicol. 2007 Sep 25;80(5):406-416. Read Abstract.
  • Kim BM, Miletich I, Mao J, McMahon AP, Sharpe PA, Shivdasani RA. Independent functions and mechanisms for homeobox gene Barx1 in patterning mouse stomach and spleen. Development. 2007 Oct;134(20):3603-13. Epub 2007 Sep 12. Read Abstract.
  • Salinas LS, Maldonado E, Macias-Silva M, Blackwell TK, Navarro RE. The DEAD box RNA helicase VBH-1 is required for germ cell function in C. elegans. Genesis. 2007 Sep;45(9):533-46. Read Abstract.
  • Zhou W, Lin L, Majumdar A, Li X, Zhang X, Liu W, Etheridge L, Shi Y, Martin J, Van de Ven W, Kaartinen V, Wynshaw-Boris A, McMahon AP, Rosenfeld MG, Evans SM. Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nat Genet. 2007 Oct;39(10):1225-34. Epub 2007 Sep 2. Read Abstract.

Diabetes

  • Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007 Sep 30. Read Abstract.
  • Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007 Sep;117(9):2553-61. Read Abstract.

Immunology

  • Monach PA, Verschoor A, Jacobs JP, Carroll MC, Wagers AJ, Benoist C, Mathis D. Circulating C3 is necessary and sufficient for induction of autoantibody-mediated arthritis in a mouse model. Arthritis Rheum. 2007 Sep;56(9):2968-74. Read Abstract.
  • Obst R, van Santen HM, Melamed R, Kamphorst AO, Benoist C, Mathis D. Sustained antigen presentation can promote an immunogenic T cell response, like dendritic cell activation. Proc Natl Acad Sci USA. 2007 Sep 25;104(39):15460-5. Epub 2007 Sep 19. Read Abstract.
  • Yamanaka KI, Dimitroff CJ, Fuhlbrigge RC, Kakeda M, Kurokawa I, Mizutani H, Kupper TS. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J Allergy Clin Immunol. 2007 Sep 29. Read Abstract.

Technology

  • Shen Y, Miller DT, Cheung SW, Lip V, Sheng X, Tomaszewicz K, Shao H, Fang H, Tang HS, Irons M, Walsh CA, Platt O, Gusella JF, Wu BL. Development of a Focused Oligonucleotide-Array Comparative Genomic Hybridization Chip for Clinical Diagnosis of Genomic Imbalance. Clin Chem. 2007 Sep 27. Read Abstract.