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Signals controlling rest and reactivation of T helper memory lymphocytes in bone marrow

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Abstract

Established views on the maintenance of immunological memory have been challenged recently by the description of memory plasma cells and memory T helper (Th) lymphocytes residing in the bone marrow (BM) in dedicated survival niches, resting in terms of proliferation and migration. While memory plasma cells are no longer reactive to antigen, memory Th lymphocytes are in a state of attentive rest, and can be reactivated fast and efficiently. Here, we discuss the signals controlling these resting states, which the memory lymphocytes receive from their microenvironment.

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Abbreviations

BM:

Bone marrow

Th:

T helper

References

  1. Manz RA, Thiel A, Radbruch A (1997) Lifetime of plasma cells in the bone marrow. Nature 388(6638):133–134

    Article  PubMed  CAS  Google Scholar 

  2. Tokoyoda K, Egawa T, Sugiyama T et al (2004) Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20(6):707–718

    Article  PubMed  CAS  Google Scholar 

  3. Chu VT, Frohlich A, Steinhauser G et al (2011) Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol 12(2):151–159

    Article  PubMed  CAS  Google Scholar 

  4. Rodriguez Gomez M, Talke Y, Goebel N et al (2010) Basophils support the survival of plasma cells in mice. J Immunol 185(12):7180–7185

    Article  PubMed  Google Scholar 

  5. Winter O, Moser K, Mohr E et al (2010) Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116(11):1867–1875

    Article  PubMed  CAS  Google Scholar 

  6. Tokoyoda K, Zehentmeier S, Hegazy AN et al (2009) Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30(5):721–730

    Article  PubMed  CAS  Google Scholar 

  7. Link A, Vogt TK, Favre S et al (2007) Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol 8(11):1255–1265

    Article  PubMed  CAS  Google Scholar 

  8. Tokoyoda K, Zehentmeier S, Chang HD et al (2009) Organization and maintenance of immunological memory by stroma niches. Eur J Immunol 39(8):2095–2099

    Article  PubMed  CAS  Google Scholar 

  9. Tokoyoda K, Hauser AE, Nakayama T et al (2010) Organization of immunological memory by bone marrow stroma. Nat Rev Immunol 10(3):193–200

    Article  PubMed  CAS  Google Scholar 

  10. Belnoue E, Pihlgren M, McGaha TL et al (2008) APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111(5):2755–2764

    Article  PubMed  CAS  Google Scholar 

  11. Yoshida T, Mei H, Dorner T et al (2010) Memory B and memory plasma cells. Immunol Rev 237(1):117–139

    Article  PubMed  CAS  Google Scholar 

  12. Garcia S, DiSanto J, Stockinger B (1999) Following the development of a CD4 T cell response in vivo: from activation to memory formation. Immunity 11(2):163–171

    Article  PubMed  CAS  Google Scholar 

  13. Grayson JM, Zajac AJ, Altman JD et al (2000) Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J Immunol 164(8):3950–3954

    PubMed  CAS  Google Scholar 

  14. Vikstrom I, Carotta S, Luthje K et al (2010) Mcl-1 is essential for germinal center formation and B cell memory. Science 330(6007):1095–1099

    Article  PubMed  CAS  Google Scholar 

  15. Smith KG, Weiss U, Rajewsky K et al (1994) Bcl-2 increases memory B cell recruitment but does not perturb selection in germinal centers. Immunity 1(9):803–813

    Article  PubMed  CAS  Google Scholar 

  16. Smith KG, Light A, O’Reilly LA et al (2000) bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J Exp Med 191(3):475–484

    Article  PubMed  CAS  Google Scholar 

  17. Kondrack RM, Harbertson J, Tan JT et al (2003) Interleukin 7 regulates the survival and generation of memory CD4 cells. J Exp Med 198(12):1797–1806

    Article  PubMed  CAS  Google Scholar 

  18. Hauser AE, Debes GF, Arce S et al (2002) Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol 169(3):1277–1282

    PubMed  CAS  Google Scholar 

  19. Fukada T, Hibi M, Yamanaka Y et al (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5(5):449–460

    Article  PubMed  CAS  Google Scholar 

  20. Tardivel A, Tinel A, Lens S et al (2004) The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF. Eur J Immunol 34(2):509–518

    Article  PubMed  CAS  Google Scholar 

  21. Hernandez-Lopez C, Valencia J, Hidalgo L et al (2008) CXCL12/CXCR4 signaling promotes human thymic dendritic cell survival regulating the Bcl-2/Bax ratio. Immunol Lett 120(1–2):72–78

    Article  PubMed  CAS  Google Scholar 

  22. Li J, Huston G, Swain SL (2003) IL-7 promotes the transition of CD4 effectors to persistent memory cells. J Exp Med 198(12):1807–1815

    Article  PubMed  CAS  Google Scholar 

  23. Mueller SN, Germain RN (2009) Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol 9(9):618–629

    PubMed  CAS  Google Scholar 

  24. Dustin ML, de Fougerolles AR (2001) Reprogramming T cells: the role of extracellular matrix in coordination of T cell activation and migration. Curr Opin Immunol 13(3):286–290

    Article  PubMed  CAS  Google Scholar 

  25. Kassiotis G, Gray D, Kiafard Z et al (2006) Functional specialization of memory Th cells revealed by expression of integrin CD49b. J Immunol 177(2):968–975

    PubMed  CAS  Google Scholar 

  26. DeNucci CC, Pagan AJ, Mitchell JS et al (2010) Control of alpha4beta7 integrin expression and CD4 T cell homing by the beta1 integrin subunit. J Immunol 184(5):2458–2467

    Article  PubMed  CAS  Google Scholar 

  27. DeNucci CC, Shimizu Y (2011) beta1 integrin is critical for the maintenance of antigen-specific CD4 T cells in the bone marrow but not long-term immunological memory. J Immunol 186(7):4019–4026

    Article  PubMed  CAS  Google Scholar 

  28. DiLillo DJ, Hamaguchi Y, Ueda Y et al (2008) Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J Immunol 180(1):361–371

    PubMed  CAS  Google Scholar 

  29. Cassese G, Arce S, Hauser AE et al (2003) Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol 171(4):1684–1690

    PubMed  CAS  Google Scholar 

  30. Manz RA, Loehning M, Cassese G et al (1998) Survival of long-lived plasma cells is independent of antigen. Int Immunol 10(11):1703–1711

    Article  PubMed  CAS  Google Scholar 

  31. Slifka MK, Antia R, Whitmire JK et al (1998) Humoral immunity due to long-lived plasma cells. Immunity 8(3):363–372

    Article  PubMed  CAS  Google Scholar 

  32. Xiang Z, Cutler AJ, Brownlie RJ et al (2007) FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol 8(4):419–427

    Article  PubMed  CAS  Google Scholar 

  33. Swain SL, Hu H, Huston G (1999) Class II-independent generation of CD4 memory T cells from effectors. Science 286(5443):1381–1383

    Article  PubMed  CAS  Google Scholar 

  34. Seddon B, Tomlinson P, Zamoyska R (2003) Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat Immunol 4(7):680–686

    Article  PubMed  CAS  Google Scholar 

  35. Herndler-Brandstetter D, Landgraf K, Jenewein B et al (2011) Human bone marrow hosts polyfunctional memory CD4+ and CD8+ T cells with close contact to IL-15-producing pells. J Immunol 186(12):6965–6971

    Article  PubMed  CAS  Google Scholar 

  36. Löhning M, Richter A, Radbruch A (2002) Cytokine memory of T helper lymphocytes. Adv Immunol 80:115–181

    Article  PubMed  Google Scholar 

  37. Zediak VP, Wherry EJ, Berger SL (2011) The contribution of epigenetic memory to immunologic memory. Curr Opin Genet Dev 21(2):154–159

    Article  PubMed  CAS  Google Scholar 

  38. Wei G, Wei L, Zhu J et al (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30(1):155–167

    Article  PubMed  Google Scholar 

  39. Lee DU, Agarwal S, Rao A (2002) Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity 16(5):649–660

    Article  PubMed  CAS  Google Scholar 

  40. Tykocinski LO, Hajkova P, Chang HD et al (2005) A critical control element for interleukin-4 memory expression in T helper lymphocytes. J Biol Chem 280(31):28177–28185

    Article  PubMed  CAS  Google Scholar 

  41. Schulz EG, Mariani L, Radbruch A et al (2009) Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12. Immunity 30(5):673–683

    Article  PubMed  CAS  Google Scholar 

  42. Richter A, Löhning M, Radbruch A (1999) Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell cycle progression. J Exp Med 190(10):1439–1450

    Article  PubMed  CAS  Google Scholar 

  43. Lederman S, Cleary AM, Yellin MJ et al (1996) The central role of the CD40-ligand and CD40 pathway in T-lymphocyte-mediated differentiation of B lymphocytes. Curr Opin Hematol 3(1):77–86

    Article  PubMed  CAS  Google Scholar 

  44. Lu Q, Wu A, Tesmer L et al (2007) Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 179(9):6352–6358

    PubMed  CAS  Google Scholar 

  45. Maciver NJ, Jacobs SR, Wieman HL et al (2008) Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol 84(4):949–957

    Article  PubMed  Google Scholar 

  46. Jacobs SR, Herman CE, Maciver NJ et al (2008) Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 180(7):4476–4486

    PubMed  CAS  Google Scholar 

  47. Ramanathan A, Schreiber SL (2009) Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA 106(52):22229–22232

    Article  PubMed  CAS  Google Scholar 

  48. Schieke SM, Phillips D, McCoy JP et al (2006) The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281(37):27643–27652

    Article  PubMed  CAS  Google Scholar 

  49. Araki K, Turner AP, Shaffer VO et al (2009) mTOR regulates memory CD8 T cell differentiation. Nature 460(7251):108–112

    Article  PubMed  CAS  Google Scholar 

  50. Rao RR, Li Q, Odunsi K et al (2010) The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32(1):67–78

    Article  PubMed  Google Scholar 

  51. Pearce EL, Walsh MC, Cejas PJ et al (2009) Enhancing CD8 T cell memory by modulating fatty acid metabolism. Nature 460(7251):103–107

    Article  PubMed  CAS  Google Scholar 

  52. Delgoffe GM, Kole TP, Zheng Y et al (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30(6):832–844

    Article  PubMed  CAS  Google Scholar 

  53. Kopf H, de la Rosa GM, Howard OM et al (2007) Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol 7(13):1819–1824

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (Grants-in-Aid: for Scientific Research on Priority Areas #22021011 and Young Scientists (A) #22689014), Uehara Memorial Foundation, Takeda Science Foundation, and Astellas Foundation for Research on Metabolic Disorders (Japan) and by Deutsche Forschungsgemeinschaft for support through SFB 650 and the BMBF for support through FORSYS (Germany). K.T. was a Research Fellow of the Alexander von Humboldt Foundation.

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Correspondence to Koji Tokoyoda.

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Tokoyoda, K., Radbruch, A. Signals controlling rest and reactivation of T helper memory lymphocytes in bone marrow. Cell. Mol. Life Sci. 69, 1609–1613 (2012). https://doi.org/10.1007/s00018-012-0969-6

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  • DOI: https://doi.org/10.1007/s00018-012-0969-6

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