Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Journal of Clinical Investigation

Volumn 120, Issue 5, 2010, Pages 1479-1493

  Matsuoka, Ken Ichi ^a,b   Kim, Haesook T ^a,c   McDonough, Sean ^a   Bascug, Gregory ^a   Warshauer, Ben ^a   Koreth, John ^a,b   Cutler, Corey ^a,b   Ho, Vincent T ^a,b   Alyea, Edwin P ^a,b   Antin, Joseph H ^a,b   Soiffer, Robert J ^a,b   Ritz, Jerome ^a,b,c,d  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^d HARVARD STEM CELL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOPHOSPHAMIDE; FAS ANTIGEN; INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 7; METHOTREXATE; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PREDNISONE; RAPAMYCIN; TACROLIMUS;

ADULT; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; APOPTOSIS; ARTICLE; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SELECTION; CLINICAL ARTICLE; CYTOKINE PRODUCTION; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; FLOW CYTOMETRY; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; LYMPHOCYTOPENIA; MALE; MYELOABLATIVE CONDITIONING; PHENOTYPE; PRIORITY JOURNAL; PROPHYLAXIS; PROSPECTIVE STUDY; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; WHOLE BODY RADIATION;

ADULT; CD4-POSITIVE T-LYMPHOCYTES; FEMALE; FORKHEAD TRANSCRIPTION FACTORS; GRAFT VS HOST DISEASE; HEMATOLOGIC NEOPLASMS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; IMMUNOLOGIC MEMORY; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; MALE; MIDDLE AGED; T-LYMPHOCYTES, REGULATORY; TRANSPLANTATION CONDITIONING; TRANSPLANTATION, HOMOLOGOUS;

EID: 77951870520     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI41072     Document Type: Article

References (79)

1. Bhatia S, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110(10):3784-3792. (Pubitemid 350159650)
2. Pidala J, Anasetti C, Jim H. Quality of life after allogeneic hematopoietic cell transplantation. Blood. 2009;114(1):7-19.
3. Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant. 2001;28(2):121-129. (Pubitemid 32725712)
4. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9(4):215-233.
5. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151-1164.
6. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057-1061. (Pubitemid 36222930)
7. Lohr J, Knoechel B, Nagabhushanam V, Abbas AK. T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens. Immunol Rev. 2005;204:116-127. (Pubitemid 40460497)
8. Sakaguchi S, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8-27.
9. Karim M, Bushell AR, Wood KJ. Regulatory T cells in transplantation. Curr Opin Immunol. 2002;14(5):584-591.
10. Wang HY, Wang RF. Regulatory T cells and cancer. Curr Opin Immunol. 2007;19(2):217-223.
11. Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006;117(3):289-300.
12. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99(10):3493-3499.
13. Edinger M, et al. CD4(+)CD25(+) regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9(9):1144-1150. (Pubitemid 37173698)
14. Trenado A, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003;112(11):1688-1696. (Pubitemid 38063726)
15. Zhao D, et al. In vivo-activated CD103+CD4+ regulatory T cells ameliorate ongoing chronic graft-versus-host disease. Blood. 2008;112(5):2129-2138.
16. Zorn E, et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106(8):2903- 2911.
17. Rieger K, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood. 2006;107(4):1717-1723. (Pubitemid 43242414)
18. Mackall CL, Hakim FT, Gress RE. T-cell regeneration: all repertoires are not created equal. Immunol Today. 1997;18(5):245-251. (Pubitemid 27219620)
19. Williams KM, Hakim FT, Gress RE. T cell immune reconstitution following lymphodepletion. Semin Immunol. 2007;19(5):318-330.
20. Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity. 2008;29(6):848-862.
21. Vukmanovic-Stejic M, et al. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest. 2006;116(9):2423-2433.
22. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775-787.
23. Liu W, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701- 1711. (Pubitemid 44036276)
24. Seddiki N, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693-1700. (Pubitemid 44036275)
25. Kimmig S, et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med. 2002;195(6):789-794. (Pubitemid 34259723)
26. Haas J, et al. Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis. J Immunol. 2007; 179(2):1322-1330.
27. Kohler S, Thiel A. Life after the thymus - CD31+ and CD31- human naive CD4+ T-cell subsets. Blood. 2008; 113(4):769-774
28. Kilpatrick RD, et al. Homeostasis of the naive CD4+ T cell compartment during aging. J Immunol. 2008;180(3):1499-1507.
29. Gerdes J, et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133(4):1710-1715. (Pubitemid 14035254)
30. Kieper WC, Jameson SC. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc Natl Acad Sci U S A. 1999;96(23):13306-13311.
31. Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000;192(4):557-564.
32. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J. Homeostasis-stimulated Proliferation Drives Naive T Cells to Differentiate Directly into Memory T Cells. J Exp Med. 2000;192(4):549-556. (Pubitemid 30666255)
33. Murali-Krishna K, Ahmed R. Cutting edge: naive T cells masquerading as memory cells. J Immunol. 2000;165(4):1733-1737. (Pubitemid 30643121)
34. Takahata Y, et al. CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp Hematol. 2004;32(7):622-629. (Pubitemid 38891531)
35. Borsellino G, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007;110(4):1225-1232. (Pubitemid 47281420)
36. Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol. 2006;176(8):4622- 4631.
37. Miyara M, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899-911.
38. Maury S, Salomon B, Klatzmann D, Cohen JL. Division rate and phenotypic differences discriminate alloreactive and nonalloreactive T cells transferred in lethally irradiated mice. Blood. 2001;98(10):3156-3158.
39. Fortner KA, Budd RC. The death receptor Fas (CD95/APO-1) mediates the deletion of T lymphocytes undergoing homeostatic proliferation. J Immunol. 2005;175(7):4374-4382.
40. Arens R, et al. Cutting edge: CD95 maintains effector T cell homeostasis in chronic immune activation. J Immunol. 2005;174(10):5915-5920. (Pubitemid 40663775)
41. Bouillet P, O'Reilly LA. CD95, BIM and T cell homeostasis. Nat Rev Immunol. 2009;9(7):514-519.
42. Alpdogan SO, et al. Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation. Blood. 2008;112(12):4755-4764.
43. Hebib NC, et al. Peripheral blood T cells generated after allogeneic bone marrow transplantation: lower levels of bcl-2 protein and enhanced sensitivity to spontaneous and CD95-mediated apoptosis in vitro. Abrogation of the apoptotic phenotype coincides with the recovery of normal naive/primed T-cell profiles. Blood. 1999;94(5):1803-1813.
44. Hoffmann P, et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006;108(13):4260-4267.
45. Fritzsching B, et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood. 2006;108(10):3371-3378.
46. van Leeuwen EM, Sprent J, Surh CD. Generation and maintenance of memory CD4(+) T Cells. Curr Opin Immunol. 2009;21(2):167-172.
47. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6(11):1142-1151. (Pubitemid 41541792)
48. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201(5):723-735. (Pubitemid 40395118)
49. Alpdogan O, et al. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2003;112(7):1095-1107. (Pubitemid 38056324)
50. Sportes C, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205(7):1701-1714. (Pubitemid 351962032)
51. Monti P, et al. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest. 2008;118(5):1806-1814. (Pubitemid 351632383)
52. Guimond M, et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009;10(2):149-157.
53. Berger C, et al. Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood. 2009;114(12):2417-2426.
54. Zhang H, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med. 2005;11(11):1238-1243. (Pubitemid 43093672)
55. Zorn E, 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. 2006;108(5):1571-1579. (Pubitemid 44316124)
56. Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107(6):2409-2414.
57. Zorn E, et al. Combined CD4+ donor lymphocyte infusion and low-dose recombinant IL-2 expand FOXP3+ regulatory T cells following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15(3):382-388.
58. Walsh PT, et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest. 2006;116(9):2521-2531.
59. Franceschini D, et al. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest. 2009;119(3):551-564.
60. Kohler S, et al. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol. 2005;35(6):1987-1994. (Pubitemid 40862347)
61. Fozza C, Nadal E, Longinotti M, Dazzi F. T-cell receptor repertoire usage after allografting differs between CD4+CD25+ regulatory T cells and their CD4+CD25- counterpart. Haematologica. 2007;92(2):206-214.
62. Kim CH. Migration and function of FoxP3+ regulatory T cells in the hematolymphoid system. Exp Hematol. 2006;34(8):1033-1040.
63. Taylor PA, et al. L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood. 2004;104(12):3804-3812.
64. Ermann J, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood. 2005;105(5):2220-2226.
65. Schneider MA, Meingassner JG, Lipp M, Moore HD, Rot A. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J Exp Med. 2007;204(4):735-745.
66. Gleeson PA, Toh BH, van Driel IR. Organ-specific autoimmunity induced by lymphopenia. Immunol Rev. 1996;149:97-125.
67. Khoruts A, Fraser JM. A causal link between lymphopenia and autoimmunity. Immunol Lett. 2005;98(1):23-31.
68. Shelburne SA, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005;19(4):399-406. (Pubitemid 40446186)
69. Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev. 2002;1(6):329-337.
70. Roep BO, et al. Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes. 1999;48(3):484-490.
71. Braghi S, Bonifacio E, Secchi A, Di Carlo V, Pozza G, Bosi E. Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes. 2000;49(2):218-224. (Pubitemid 30071000)
72. Dudley ME, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850-854.
73. Rapoport AP, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med. 2005;11(11):1230-1237.
74. Wu Z, et al. Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med. 2004;10(1):87-92. (Pubitemid 38524703)
75. King C, Ilic A, Koelsch K, Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004;117(2):265-277. (Pubitemid 38496245)
76. Krupica T Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. 2006;120(2):121-128.
77. Le Saout C, Mennechet S, Taylor N, Hernandez J. Memory-like CD8 + and CD4+ T cells cooperate to break peripheral tolerance under lymphopenic conditions. Proc Natl Acad Sci U S A. 2008; 105(49):19414-19419.
78. Shen S, et al. Control of homeostatic proliferation by regulatory T cells. J Clin Invest. 2005;115(12):3517-3526. (Pubitemid 43121839)
79. Winstead CJ, Fraser JM, Khoruts A. Regulatory CD4+CD25+Foxp3+ T cells selectively inhibit the spontaneous form of lymphopenia-induced proliferation of naive T cells. J Immunol. 2008;180(11):7305-7317.