Regulatory T cells in HIV immunotherapy

HIV Therapy

Volumn 4, Issue 6, 2010, Pages 639-647

  Macatangay, Bernard J C ^a   Rinaldo, Charles R ^b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

HIV; immunotherapy; Treg

Indexed keywords

ANTIRETROVIRUS AGENT; DACLIZUMAB; DENDRITIC CELL VACCINE; HUMAN IMMUNODEFICIENCY VIRUS VACCINE; INTERLEUKIN 12; INTERLEUKIN 28B; RECOMBINANT ALPHA INTERFERON; RECOMBINANT INTERLEUKIN 2; RECOMBINANT INTERLEUKIN 7; TRANSCRIPTION FACTOR FOXP3;

ADAPTIVE IMMUNITY; CD4 LYMPHOCYTE COUNT; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELLULAR IMMUNITY; CYTOKINE PRODUCTION; CYTOTOXIC LYMPHOCYTE; DENDRITIC CELL; DNA IMMUNIZATION; FOLLOW UP; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOPATHOGENESIS; IMMUNOTHERAPY; LYMPHOCYTE PROLIFERATION; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; VACCINATION; VIRUS INHIBITION;

EID: 78650537096     PISSN: 17584310     EISSN: None     Source Type: Journal    
DOI: 10.2217/hiv.10.51     Document Type: Review

References (85)

1. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155(3), 1151-1164 (1995). Seminal study that first described a subset of T cells that function to maintain self-tolerance by downregulating the immune response to self antigens.
2. + T cells as a functionally and phenotypically distinct immunoregulatory T-cell subpopulation. Int. Immunol. 12(8), 1145-1155 (2000).
3. Taams L, Akbar AN, Wauben MHM (Eds): Regulatory T Cells In Inflammation. Birkhäuser, Basel, Switzerland (2005).
4. von Herrath MG, Harrison LC: Antigen-induced regulatory T cells in autoimmunity. Nat. Rev. Immunol. 3(3), 223-232 (2003).
5. Belkaid Y, Tarbell K: Regulatory T cells in the control of host-microorganism interactions (*). Annu. Rev. Immunol. 27, 551-589 (2009). Extensive review on the role of regulatory T cells (Treg) in different infections and includes a discussion of different strategies of Treg manipulation as immunotherapy.
6. Sakaguchi S, Miyara M, Costantino CM, Hafler DA: FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10(7), 490-500 (2010).
7. + naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162(9), 5317-5326 (1999).
8. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609), 1057-1061 (2003).
9. + regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192(2), 303-310 (2000).
10. + immunoregulatory T cells: gene expression ana lysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16(2), 311-323 (2002).
11. Mandapathil M, Szczepanski MJ, Szajnik M et al.: Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J. Biol. Chem. 285(36), 27571-27580 (2010).
12. Mandapathil M, Lang S, Gorelik E, Whiteside TL: Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression. J. Immunol. Methods. 346(1-2), 55-63 (2009). Described another method of isolating functionally suppressive Treg without using the intracellular staining with forkhead box (FOX)P3.
13. + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4), 1225-1232 (2007).
14. + T cells for IL-2 and exploit it for the induction of IL-10 production. Int. Immunol. 17(3), 279-288 (2005).
15. + T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J. Immunol. 172(7), 4100-4110 (2004).
16. Sojka DK, Huang YH, Fowell DJ: Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology 124(1), 13-22 (2008).
17. Cao X, Cai SF, Fehniger TA et al.: Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27(4), 635-646 (2007).
18. Fazekas de St Groth B, Landay AL: Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response? AIDS 22(6), 671-683 (2008). Lists both murine and human studies in Treg identification and summarizes important Treg studies in HIV infection.
19. Seddiki N, Kelleher AD: Regulatory T cells in HIV infection: who's suppressing what? Curr HIV/AIDS Rep. 5(1), 20-26 (2008).
20. + Treg in lymph nodes compared with Treg in peripheral blood and demonstrated that the lymph nodes Treg exhibited potent HIV-specific suppressive function.
21. Krathwohl MD, Schacker TW, Anderson JL: Abnormal presence of semimature dendritic cells that induce regulatory T cells in HIV-infected subjects. J. Infect. Dis. 193(4), 494-504 (2006).
22. + regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression. Int. Immunol. 21(3), 283-294 (2009). Demonstrates how HIV binding to Treg causes a two- to five-fold increase in Treg suppressive activity, an increase in Treg survival, and an accumulation of Treg in peripheral and mucosal lymphoid tissue.
23. + regulatory T cells. Blood 114(6), 1263-1269 (2009).
24. + T cells in vitro. AIDS Res. Hum. Retroviruses 23(3), 438-450 (2007).
25. + Treg suppression compensates for reduced Treg number in asymptomatic HIV-1 infection. PLoS ONE 5(2), E9254 (2010).
26. + T cell activation levels in primary HIV-1 infection. J. Leukoc. Biol. 83(2), 254-262 (2008).
27. + T cells in HIV-1-infected typical progressors, but not in long-term non-progressors. Immunology 128(1 Suppl.), E366-E375 (2009).
28. Giorgi JV, Hultin LE, McKeating JA et al.: Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 179(4), 859-870 (1999). One of the first studies correlating immune activation with HIV disease progression.
29. Cecchinato V, Tryniszewska E, Ma ZM et al.: Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J. Immunol. 180(8), 5439-5447 (2008).
30. Weiss L, Piketty C, Assoumou L et al.: Relationship between regulatory T cells and immune activation in human immunodeficiency virus-infected patients interrupting antiretroviral therapy. PLoS ONE 5(7), E11659 (2010). Demonstrated the dual role of Treg in HIV infection: decreasing immune activation and suppressing immune response to the virus.
31. Brenchley JM, Paiardini M, Knox KS et al.: Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112(7), 2826-2835 (2008).
32. Favre D, Lederer S, Kanwar B et al.: Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog. 5(2), E1000295 (2009). Highly important study demonstrating the negative correlation of T-helper (Th)17:Treg ratio with sustained systemic immune activation in the blood and lymph nodes of pigtailed macaques infected with simian immunodeficiency virus (SIV). The study highlights the possible roles Treg and Th17 cells play in lentiviral infections.
33. + Th17 cells and gradual decline in regulatory T cells. AIDS 24(4), 491-502 (2010).
34. Favre D, Mold J, Hunt PW et al.: Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of Th17 to regulatory T cells in HIV disease. Sci. Transl. Med. 2(32), 32ra36 (2010). Important follow-up study investigating the role of indoleamine 2,3 deoxygenase in altering the Th17/Treg balance and in the chronic inflammatory state observed in progressive HIV disease.
35. Cao W, Jamieson BD, Hultin LE, Hultin PM, Detels R: Regulatory T cell expansion and immune activation during untreated HIV type 1 infection are associated with disease progression. AIDS Res. Hum. Retroviruses 25(2), 183-191 (2009). Case-control study results showed positive correlation of Treg expansion leading to immune activation and disease progression.
36. Kovacs JA, Baseler M, Dewar RJ et al.: Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N. Engl. J. Med. (9), 567-575 (1995).
37. Kovacs JA, Vogel S, Albert JM et al.: Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N. Engl. J. Med. 335(18), 1350-1356 (1996).
38. + T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248). J. Acquir. Immune Defic. Syndr. 36(1), 576-587 (2004).
39. Goujard C, Marcellin F, Hendel-Chavez H et al.: Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 randomized study. AIDS Res. Hum. Retroviruses 23(9), 1105-1113 (2007).
40. Abrams D, Levy Y, Losso MH et al.: Interleukin-2 therapy in patients with HIV infection. N. Engl. J. Med. 361(16), 1548-1559 (2009).
41. Asmuth DM, Murphy RL, Rosenkranz SL et al.: Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon α-2a in HIV-1-monoinfected participants: a Phase II clinical trial. J. Infect. Dis. 201(11), 1686-1696 (2010).
42. Levy Y, Lacabaratz C, Weiss L et al.: Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J. Clin. Invest. 119(4), 997-1007 (2009).
43. Sereti I, Dunham RM, Spritzler J et al.: IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 113(25), 6304-6314 (2009).
44. Day CL, Kaufmann DE, Kiepiela P et al.: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443(7109), 350-354 (2006).
45. + T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10(1), 29-37 (2009).
46. Macatangay BJ, Rinaldo CR: PD-1 blockade: a promising immunotherapy for HIV? Cellscience 5(4), 61-65 (2009).
47. + T cell function by multiple costimulatory receptors during chronic HIV infection. J. Immunol. 185(5), 3007-3018 (2010). Investigated the relationship of different costimulatory receptors with HIV replication and found that expression of programmed death receptor (PD)-1, cytotoxic T lymphocyte-associated antigen (CTLA)-4 and T-cell immunoglobulin and mucin domain-containing molecule (TIM)-3 together strongly correlated with plasma viremia.
48. Velu V, Titanji K, Zhu B et al.: Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458(7235), 206-210 (2009). First in vivo study showing the enhancement of SIV-specific immune response after administering a PD-1 antibody to SIV-infected macaques.
49. + T cells from HIV-1-infected individuals. J. Clin. Immunol. 29(5), 637-645 (2009).
50. Connolly NC, Whiteside TL, Wilson C, Kondragunta V, Rinaldo CR, Riddler SA: Therapeutic immunization with human immunodeficiency virus type 1 (HIV-1) peptide-loaded dendritic cells is safe and induces immunogenicity in HIV-1-infected individuals. Clin. Vaccine Immunol. 15(2), 284-292 (2008).
51. Routy JP, Boulassel MR, Yassine-Diab B et al.: Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin. Immunol. 134(2), 140-147 (2010).
52. Lu W, Arraes LC, Ferreira WT, Andrieu JM: Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat. Med. 10(12), 1359-1365 (2004).
53. Garcia F, Lejeune M, Climent N et al.: Therapeutic immunization with dendritic cells loaded with heat-inactivated autologous HIV-1 in patients with chronic HIV-1 infection. J. Infect. Dis. 191(10), 1680-1685 (2005).
54. + T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res. 67(15), 7487-7494 (2007). Cancer study showing proliferation of existent Treg after administration of IL-2 therapy together with increased C-X-C chemokine receptor-4 expression allowing them to migrate to the tumor.
55. + regulatory T cell populations in interleukin-2-treated HIV patients. Proc. Natl Acad. Sci. USA 107(23), 10632-10637 (2010). Demonstrated expansion of the Treg subset after IL-2 therapy, which the authors hypothesize is a possible explanation for the higher relative risk of progression to AIDS in subjects who had greater CD4 count expansion while on IL-2 therapy.
56. + T (T(H)17) cells in the periphery. J. Clin. Immunol. 30(5), 681-692 (2010).
57. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG: IFN-a and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 166(9), 5530-5539 (2001).
58. Luik A, Knapp S, Thursz M, Thomas HC, Schlaak JF: Autoregulatory role of interleukin-10 in hepatitis C patients treated with IFN-α. J. Interferon Cytokine Res. 24(10), 585-593 (2004).
59. + Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J. Clin. Invest. 119(3), 551-564 (2009).
60. Radziewicz H, Dunham RM, Grakoui A: PD-1 tempers Tregs in chronic HCV infection. J. Clin. Invest. 119(3), 450-453 (2009).
61. Sachdeva M, Fischl MA, Pahwa R, Sachdeva N, Pahwa S: Immune exhaustion occurs concomitantly with immune activation and decrease in regulatory T cells in viremic chronically HIV-1-infected patients. J. Acquir. Immune Defic. Syndr. 54(5), 447-454 (2010). Showed that in viremic HIV patients, Treg frequency negatively correlated with both immune activation (HLA-DR and CD38 coexpression) and immune exhaustion (expression of PD-1).
62. Amarnath S, Costanzo CM, Mariotti J et al.: Regulatory T cells and human myeloid dendritic cells promote tolerance via programmed death ligand-1. PLoS Biol. 8(2), E1000302 (2010). Demonstrated an important mechanism of suppression by Treg, which is to upregulate the expression of PD-L1 in myeloid dendritic cells.
63. Macatangay BJ, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR: Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS ONE 5(3), e9852 (2010). Demonstrated increase in HIV-specific Treg suppressive function in HIV subjects after receiving an autologous dendritic cell HIV vaccine. The removal of Treg led to an increase on CD8 T-cell polyfunctional response to Gag peptide.
64. Banerjee DK, Dhodapkar MV, Matayeva E, Steinman RM, Dhodapkar KM: Expansion of FOXP3 high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood 108(8), 2655-2661 (2006). Cancer study that demonstrated that dendritic cells can induce the expansion of Treg and is dependent on cell-cell contact.
65. + regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2. J. Immunother. 33(4), 425-434 (2010).
66. + natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc. Natl Acad. Sci. USA 105(29), 10113-10118 (2008). Another important study demonstrating Treg and dendritic cell interactions. Treg were shown to aggregate around the dendritic cells and exert a CD80/86 down modulating effect, even in the presence of strong dendritic cell-maturing stimuli.
67. O'Gorman WE, Dooms H, Thorne SH et al.: The initial phase of an immune response functions to activate regulatory T cells. J. Immunol. 183(1), 332-339 (2009). Important study demonstrating the activation of Treg as the initial event in the T-cell immune response.
68. Valentin A, von Gegerfelt A, Rosati M et al.: Repeated DNA therapeutic vaccination of chronically SIV-infected macaques provides additional virological benefit. Vaccine 8(8), 1962-1974 (2010).
69. Rech AJ, Vonderheide RH: Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann. NY Acad. Sci. 1174, 99-106 (2009).
70. Jacobs JF, Punt CJ, Lesterhuis WJ et al.: Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a Phase I/II study in metastatic melanoma patients. Clin. Cancer Res. 16(20), 5067-5078 (2010).
71. Saha A, Chatterjee SK: Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer. Scand. J. Immunol. 71(2), 70-82 (2010).
72. Coe D, Begom S, Addey C, White M, Dyson J, Chai JG: Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol. Immunother. 59(9), 1367-1377 (2010).
73. Morrow MP, Pankhong P, Laddy DJ et al.: Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. Blood 113(23), 5868-5877 (2009).
74. Hryniewicz A, Boasso A, Edghill-Smith Y et al.: CTLA-4 blockade decreases TGF-β, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood 108(12), 3834-3842 (2006).
75. Sarnaik AA, Weber JS: Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J. 15(3), 169-173 (2009).
76. Hershfield MS. New insights into adenosine-receptor- mediated immunosuppression and the role of adenosine in causing the immunodeficiency associated with adenosine deaminase deficiency. Eur. J. Immunol. 35(1), 25-30 (2005).
77. Deaglio S, Dwyer KM, Gao W et al.: Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204(6), 1257-1265 (2007).
78. Douek DC, Roederer M, Koup RA: Emerging concepts in the immunopathogenesis of AIDS. Annu. Rev. Med. 60, 471-484 (2009). Excellent review of recent developments in HIV immunopathogenesis, which includes chronic immune activation and T-cell dysfunction.
79. Thomson CW, Lee BP, Zhang L: Double-negative regulatory T cells: non-conventional regulators. Immunol. Res. 35(1-2), 163-178 (2006).
80. Bouaziz JD, Yanaba K, Tedder TF: Regulatory B cells as inhibitors of immune responses and inflammation. Immunol. Rev. 224, 201-214 (2008).
81. Gabrilovich DI, Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9(3), 162-174 (2009).
82. Scholzen A, Minigo G, Plebanski M: Heroes or villains? T regulatory cells in malaria infection. Trends Parasitol. 26(1), 16-25 (2010).
83. He XY, Xiao L, Chen HB et al.: T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients. Eur. J. Clin. Microbiol. Infect. Dis. 29(6), 643-650 (2010).
84. Sturm N, Thelu MA, Camous X et al.: Characterization and role of intra-hepatic regulatory T cells in chronic hepatitis C pathogenesis. J. Hepatol. 53(1), 25-35 (2010).
85. Rallon NI, Barreiro P, Soriano V, Garcia-Samaniego J, Lopez M, Benito JM: Elevated TGF-β1 levels might protect HCV/HIV-coinfected patients from liver fibrosis. Eur. J. Clin. Invest. DOI: 10.1111/j.1365-2362.2010.02381 (2010) (Epub ahead of print).