Interleukin-21 and T follicular helper cells in HIV infection: Research focus and future perspectives

Immunologic Research

Volumn 57, Issue 1-3, 2013, Pages 279-291

  Pallikkuth, Suresh ^a   Pahwa, Savita ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

HIV and IL 21; HIV persistence; IL 21 and B cells; IL 21 and immunity; IL 21 and T cells; Tfh cells

Indexed keywords

IMMUNOMODULATING AGENT; INTERLEUKIN 21;

AGING; ARTICLE; HELPER CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOMODULATION; IN VIVO STUDY; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; T LYMPHOCYTE;

AGING; ANIMALS; B-LYMPHOCYTES; CYTOTOXICITY, IMMUNOLOGIC; HIV INFECTIONS; HIV-1; HUMANS; IMMUNITY, HUMORAL; IMMUNOLOGIC FACTORS; INTERLEUKINS; KILLER CELLS, NATURAL; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 84891495340     PISSN: 0257277X     EISSN: 15590755     Source Type: Journal    
DOI: 10.1007/s12026-013-8457-0     Document Type: Article

References (150)

1. Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ, et al. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol (Baltimore, Md: 1950). 2007;178:2827-34.
2. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57-63.
3. Wei L, Laurence A, Elias KM, O'Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem. 2007;282:34605-10.
4. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138-49.
5. Mittal A, Murugaiyan G, Beynon V, Hu D, Weiner HL. IL-27 induction of IL-21 from human CD8 + T cells induces granzyme B in an autocrine manner. Immunol Cell Biol. 2012;90:831-5.
6. Williams LD, Bansal A, Sabbaj S, Heath SL, Song W, Tang J, et al. Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J Virol. 2011;85:2316-24.
7. Jin H, Carrio R, Yu A, Malek TR. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol (Baltimore, Md: 1950). 2004;173:657-65.
8. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci USA. 2000;97:11439-44.
9. Brandt K, Bulfone-Paus S, Jenckel A, Foster DC, Paus R, Ruckert R. Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo. J Invest Dermatol. 2003;121:1379-82.
10. Caruso R, Fina D, Peluso I, Fantini MC, Tosti C, Del Vecchio Blanco G, et al. IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis. J Immunol (Baltimore, Md: 1950). 2007;178:5957-65.
11. Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al. Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut. 2006;55:1774-80.
12. Ruckert R, Bulfone-Paus S, Brandt K. Interleukin-21 stimulates antigen uptake, protease activity, survival and induction of CD4 + T cell proliferation by murine macrophages. Clin Exp Immunol. 2008;151:487-95.
13. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, et al. Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol (Baltimore, Md: 1950). 2001;167:1-5.
14. Pahwa S. Role of common gamma chain utilizing cytokines for immune reconstitution in HIV infection. Immunol Res. 2007;38:373-86.
15. Pallikkuth S, Parmigiani A, Pahwa S the role of interleukin-21 in HIV infection. Cytokine Growth Factor Rev. 2012;23:173-80.
16. Craiu A, Barouch DH, Zheng XX, Kuroda MJ, Schmitz JE, Lifton MA, et al. An IL-2/Ig fusion protein influences CD4 + T lymphocytes in naive and simian immunodeficiency virus-infected Rhesus monkeys. AIDS Res Hum Retrovir. 2001;17:873-86.
17. Villinger F, Miller R, Mori K, Mayne AE, Bostik P, Sundstrom JB, et al. IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques. Vaccine. 2004;22:3510-21.
18. Mueller YM, Petrovas C, Bojczuk PM, Dimitriou ID, Beer B, Silvera P, et al. Interleukin-15 increases effector memory CD8 + t cells and NK Cells in simian immunodeficiency virus-infected macaques. J Virol. 2005;79:4877-85.
19. Picker LJ, Reed-Inderbitzin EF, Hagen SI, Edgar JB, Hansen SG, Legasse A, et al. IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. J Clin Investig. 2006;116:1514-24.
20. Beq S, Nugeyre MT, Ho Tsong Fang R, Gautier D, Legrand R, Schmitt N, et al. IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy. J Immunol (Baltimore, Md: 1950). 2006;176:914-22.
21. Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood. 2003;101:2294-9.
22. Moniuszko M, Edghill-Smith Y, Venzon D, Stevceva L, Nacsa J, Tryniszewska E, et al. Decreased number of CD4 + and CD8 + T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques. Virology. 2006;356:188-97.
23. Pallikkuth S, Micci L, Ende ZS, Iriele RI, Cervasi B, Lawson B, et al. Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL)-21. PLoS Pathog. 2013;9:e1003471.
24. Pallikkuth S, Rogers K, Villinger F, Dosterii M, Vaccari M, Franchini G, et al. Interleukin-21 administration to rhesus macaques chronically infected with simian immunodeficiency virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replication. Vaccine. 2011;29:9229-38.
25. Vassena L, Miao H, Cimbro R, Malnati MS, Cassina G, Proschan MA, et al. Treatment with IL-7 prevents the decline of circulating CD4 + T cells during the acute phase of SIV infection in rhesus macaques. PLoS Pathog. 2012;8:e1002636.
26. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelievre JD, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Investig. 2009;119:997-1007.
27. Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood. 2009;113:6304-14.
28. Levy Y, Sereti I, Tambussi G, Routy JP, Lelievre JD, Delfraissy JF, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012;55:291-300.
29. Vandergeeten C, Fromentin R, DaFonseca S, Lawani MB, Sereti I, Lederman MM, et al. Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood. 2013;121:4321-9.
30. Mueller YM, Do DH, Altork SR, Artlett CM, Gracely EJ, Katsetos CD, et al. IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8 + T cell responses. J Immunol (Baltimore, Md: 1950). 2008;180:350-60.
31. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. IL-21 enhances and sustains CD8 + T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol (Baltimore, Md: 1950). 2004;173:900-9.
32. Li Y, Bleakley M, Yee C. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J Immunol (Baltimore, Md: 1950). 2005;175:2261-9.
33. White L, Krishnan S, Strbo N, Liu H, Kolber MA, Lichtenheld MG, et al. Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood. 2007;109:3873-80.
34. Parmigiani A, Pallin MF, Schmidtmayerova H, Lichtenheld MG, Pahwa S. Interleukin-21 and cellular activation concurrently induce potent cytotoxic function and promote antiviral activity in human CD8 T cells. Hum Immunol. 2011;72:115-23.
35. Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, et al. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity. 2007;26:798-811.
36. Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ, et al. HIV-1-specific interleukin-21 + CD4 + T cell responses contribute to durable viral control through the modulation of HIV-specific CD8 + T cell function. J Virol. 2011;85:733-41.
37. Yue FY, Lo C, Sakhdari A, Lee EY, Kovacs CM, Benko E, et al. HIV-specific IL-21 producing CD4 + T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control. J Immunol (Baltimore, Md: 1950). 2010;185:498-506.
38. Iannello A, Boulassel MR, Samarani S, Tremblay C, Toma E, Routy JP, et al. IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication. J Leukoc Biol. 2010;87:857-67.
39. Metzger DW. Interleukin-12 as an adjuvant for induction of protective antibody responses. Cytokine. 2010;52:102-7.
40. Kalams SA, Parker SD, Elizaga M, Metch B, Edupuganti S, Hural J, et al. Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery. J Infect Dis. 2013;208:818-29.
41. Lindsay RW, Ouellette I, Arendt HE, Martinez J, Destefano J, Lopez M, et al. SIV antigen-specific effects on immune responses induced by vaccination with DNA electroporation and plasmid IL-12. Vaccine. 2013;31:4749-58.
42. Naderi M, Saeedi A, Moradi A, Kleshadi M, Zolfaghari MR, Gorji A, et al. Interleukin-12 as a genetic adjuvant enhances hepatitis C virus NS3 DNA vaccine immunogenicity. Virologica Sinica. 2013;28:167-73.
43. Rodriguez AM, Pascutti MF, Maeto C, Falivene J, Holgado MP, Turk G, et al. IL-12 and GM-CSF in DNA/MVA immunizations against HIV-1 CRF12-BF Nef induced T-cell responses with an enhanced magnitude, breadth and quality. PLoS ONE. 2012;7:e37801.
44. Villinger F, Bucur S, Chikkala NF, Brar SS, Bostik P, Mayne AE, et al. In vitro and in vivo responses to interleukin 12 are maintained until the late SIV infection stage but lost during AIDS. AIDS Res Hum Retrovir. 2000;16:751-63.
45. Watanabe N, Sypek JP, Mittler S, Reimann KA, Flores-Villanueva P, Voss G, et al. Administration of recombinant human interleukin 12 to chronically SIVmac-infected rhesus monkeys. AIDS Res Hum Retrovir. 1998;14:393-9.
46. Ma CS, Suryani S, Avery DT, Chan A, Nanan R, Santner-Nanan B, et al. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol Cell Biol. 2009;87:590-600.
47. Nurieva RI, Dong C. (IL-)12 and 21: a new kind of help in the follicles. Immunol Cell Biol. 2009;87:577-8.
48. Schmitt N, Morita R, Bourdery L, Bentebibel SE, Zurawski SM, Banchereau J, et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity. 2009;31:158-69.
49. Alter G, Altfeld M. NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J Intern Med. 2009;265:29-42.
50. Tiemessen CT, Shalekoff S, Meddows-Taylor S, Schramm DB, Papathanasopoulos MA, Gray GE, et al. Natural killer cells that respond to human immunodeficiency virus type 1 (HIV-1) peptides are associated with control of HIV-1 infection. J Infect Dis. 2010;202:1444-53.
51. Strbo N, de Armas L, Liu H, Kolber MA, Lichtenheld M, Pahwa S. IL-21 augments natural killer effector functions in chronically HIV-infected individuals. AIDS (London, England). 2008;22:1551-60.
52. Sarra M, Franze E, Pallone F, Monteleone G. Targeting interleukin-21 in inflammatory diseases. Expert Opin Ther Targets. 2011;15:695-702.
53. Sondergaard H, Skak K. IL-21: roles in immunopathology and cancer therapy. Tissue Antigens. 2009;74:467-79.
54. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008;26:57-79.
55. Yuan FL, Hu W, Lu WG, Li X, Li JP, Xu RS, et al. Targeting interleukin-21 in rheumatoid arthritis. Mol Biol Rep. 2011;38:1717-21.
56. Hashmi MH, Van Veldhuizen PJ. Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma. Expert Opin Biol Ther. 2010;10:807-17.
57. Davis ID, Brady B, Kefford RF, Millward M, Cebon J, Skrumsager BK, et al. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial. Clin Cancer Res. 2009;15:2123-9.
58. Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res. 2007;13:3630-6.
59. Frederiksen KS, Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, et al. IL-21 induces in vivo immune activation of NK cells and CD8(+) T cells in patients with metastatic melanoma and renal cell carcinoma. Cancer Immunol Immunother. 2008;57:1439-49.
60. Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol. 2008;26:2034-9.
61. Yi JS, Ingram JT, Zajac AJ. IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection. J Immunol (Baltimore, Md: 1950). 2010;185:4835-45.
62. Novy P, Huang X, Leonard WJ, Yang Y. Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection. J Immunol (Baltimore, Md: 1950). 186:2729-38.
63. Rasheed MA, Latner DR, Aubert RD, Gourley T, Spolski R, Davis CW, et al. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol. 2013;87:7737-46.
64. Karnowski A, Chevrier S, Belz GT, Mount A, Emslie D, D'Costa K, et al. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J Exp Med. 2012;209:2049-64.
65. Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science (New York, NY). 2009;324:1569-72.
66. Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science (New York, NY). 2009;324:1576-80.
67. Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a chronic viral infection. Science (New York, NY). 2009;324:1572-6.
68. Schmitz I, Schneider C, Frohlich A, Frebel H, Christ D, Leonard WJ, et al. IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS Pathog. 2013;9:e1003362.
69. Pawlak K, Mysliwiec M, Pawlak D. Interleukin-21 in hemodialyzed patients: association with the etiology of chronic kidney disease and the seropositivity against hepatitis C virus infection. Clin Biochem. 2011;44:1416-20.
70. Franks I. Viral hepatitis: interleukin 21 has a key role in age-dependent response to HBV. Nat Rev Gastroenterol Hepatol. 2011;8:243.
71. Ma SW, Huang X, Li YY, Tang LB, Sun XF, Jiang XT, et al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. J Hepatol. 2012;56:775-81.
72. Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang ZE, Avanesyan L, et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest. 2011;121:1154-62.
73. Ma Z, Xie Y, Wang Y, Ma L, He Y, Zhang Y, et al. Peripheral blood CD4(+);CXCR5(+); follicular helper T cells are related to hyperglobulinemia of patients with chronic hepatitis B. Xi bao yu fen zi mian yi xue za zhi Chin J Cell Mol Immunol. 2013;29:515-8, 21.
74. Kared H, Fabre T, Bedard N, Bruneau J, Shoukry NH. Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog. 2013;9:e1003422.
75. Li L, Liu M, Cheng L, Gao X, Fu J, Kong G, et al. HBcAg-specific IL-21 producing-CD4 + T cells are associated with relative viral control in patients with chronic hepatitis B. Scand J Immunol. 2013;78:439-46.
76. Li N, Zhu Q, Li Z, Han Q, Chen J, Lv Y, et al. IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection. Hum Immunol. 2013;74:567-73.
77. Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K, Smith EC, et al. CD4 T follicular helper cell dynamics during SIV infection. J Clin Investig. 2012;122:3281-94.
78. Nutt SL, Tarlinton DM. Germinal center B and follicular helper T cells: siblings, cousins or just good friends? Nat Immunol. 2011;12:472-7.
79. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429-57.
80. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS ONE. 2011;6:e17739.
81. Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010;207:353-63.
82. Spolski R, Leonard WJ. IL-21 and T follicular helper cells. Int Immunol. 2009;22:7-12.
83. Recher M, Berglund LJ, Avery DT, Cowan MJ, Gennery AR, Smart J, et al. IL-21 is the primary common gamma chain-binding cytokine required for human B-cell differentiation in vivo. Blood. 2011;118:6824-35.
84. Liu YJ, Zhang J, Lane PJ, Chan EY, MacLennan IC. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur J Immunol. 1991;21:2951-62.
85. Jacob J, Kassir R, Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I the architecture and dynamics of responding cell populations. J Exp Med. 1991;173:1165-75.
86. Inamine A, Takahashi Y, Baba N, Miyake K, Tokuhisa T, Takemori T, et al. Two waves of memory B-cell generation in the primary immune response. Int Immunol. 2005;17:581-9.
87. Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010;207:365-78.
88. Lee SK, Rigby RJ, Zotos D, Tsai LM, Kawamoto S, Marshall JL, et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med. 2011;208:1377-88.
89. Odegard JM, Marks BR, DiPlacido LD, Poholek AC, Kono DH, Dong C, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med. 2008;205:2873-86.
90. Tellier J, Nutt SL the unique features of follicular T cell subsets. Cell Mol Life Sci. 2013. doi: 10.1007/s00018-013-1420-3.
91. Haynes NM, Allen CD, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J Immunol. 2007;179:5099-108.
92. Hardtke S, Ohl L, Forster R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood. 2005;106:1924-31.
93. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621-63.
94. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol (Baltimore, Md: 1950). 2004;173:68-78.
95. Luthje K, Kallies A, Shimohakamada Y, Belz GT, Light A, Tarlinton DM, et al the development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat Immunol. 2012;13:491-8.
96. Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol (Baltimore, Md: 1950). 2009;183:797-801.
97. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science (New York, NY). 2009;325:1001-5.
98. Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, et al. Bcl6 and maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol (Baltimore, Md: 1950). 2012;188:3734-44.
99. Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity. 2009;30:324-35.
100. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science (New York, NY). 2009;325:1006-10.
101. Mehta DS, Wurster AL, Whitters MJ, Young DA, Collins M, Grusby MJ. IL-21 induces the apoptosis of resting and activated primary B cells. J Immunol (Baltimore, Md: 1950). 2003;170:4111-8.
102. Pallikkuth S, Parmigiani A, Pahwa S. Role of IL-21 and IL-21 receptor on B cells in HIV infection. Crit Rev Immunol. 2012;32:173-95.
103. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol (Baltimore, Md: 1950). 2005;175:7867-79.
104. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34:108-21.
105. Rankin AL, MacLeod H, Keegan S, Andreyeva T, Lowe L, Bloom L, et al. IL-21 receptor is critical for the development of memory B cell responses. J Immunol (Baltimore, Md: 1950). 2011;186:667-74.
106. Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, Chew GY, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010;207:155-71.
107. Kurosaki T, Shinohara H, Baba Y. B cell signaling and fate decision. Annu Rev Immunol. 2010;28:21-55.
108. Bryant VL, Ma CS, Avery DT, Li Y, Good KL, Corcoran LM, et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5 + T follicular helper cells. J Immunol (Baltimore, Md: 1950). 2007;179:8180-90.
109. Diehl SA, Schmidlin H, Nagasawa M, van Haren SD, Kwakkenbos MJ, Yasuda E, et al. STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation. J Immunol (Baltimore, Md: 1950). 2008;180:4805-15.
110. Moir S, Fauci AS. B cells in HIV infection and disease. Nat Rev Immunol. 2009;9:235-45.
111. van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, Peretz Y, et al. Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis. J Clin Investig. 2011;121:3877-88.
112. Amu S, Ruffin N, Rethi B, Chiodi F. Impairment of B-cell functions during HIV-1 infection. AIDS (London, England). 2013;27:2323-34.
113. Moir S, Fauci AS. Insights into B cells and HIV-specific B-cell responses in HIV-infected individuals. Immunol Rev. 2013;254:207-24.
114. Malaspina A, Moir S, Orsega SM, Vasquez J, Miller NJ, Donoghue ET, et al. Compromised B cell responses to influenza vaccination in HIV-infected individuals. J Infect Dis. 2005;191:1442-50.
115. Moir S, Malaspina A, Ho J, Wang W, Dipoto AC, O'Shea MA, et al. Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. J Infect Dis. 2008;197:572-9.
116. Iannello A, Boulassel MR, Samarani S, Debbeche O, Tremblay C, Toma E, et al. Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study. J Immunol (Baltimore, Md: 1950). 2010;184:114-26.
117. Iannello A, Tremblay C, Routy JP, Boulassel MR, Toma E, Ahmad A. Decreased levels of circulating IL-21 in HIV-infected AIDS patients: correlation with CD4 + T-cell counts. Viral Immunol. 2008;21:385-8.
118. Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR, McHeyzer-Williams LJ, et al. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat Immunol. 2007;8:753-61.
119. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur J Immunol. 2006;36:1892-903.
120. Hale JS, Youngblood B, Latner DR, Mohammed AU, Ye L, Akondy RS, et al. Distinct memory CD4 + T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity. 2013;38:805-17.
121. Weber JP, Fuhrmann F, Hutloff A. T-follicular helper cells survive as long-term memory cells. Eur J Immunol. 2012;42:1981-8.
122. Schaerli P, Loetscher P, Moser B. Cutting edge: induction of follicular homing precedes effector Th cell development. J Immunol (Baltimore, Md: 1950). 2001;167:6082-6.
123. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000;192:1553-62.
124. Forster R, Emrich T, Kremmer E, Lipp M. Expression of the G-protein-coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood. 1994;84:830-40.
125. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996;87:1037-47.
126. Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. Subspecialization of CXCR5 + T cells: B helper activity is focused in a germinal center-localized subset of CXCR5 + T cells. J Exp Med. 2001;193:1373-81.
127. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745-63.
128. Pallikkuth S, Parmigiani A, Silva SY, George VK, Fischl M, Pahwa R, et al. Impaired peripheral blood T-follicular helper cell function in HIV-infected non-responders to the 2009 H1N1/09 vaccine. Blood. 2012;120:985-93.
129. Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, et al. Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity. 2011;35:633-46.
130. MacLeod MK, David A, McKee AS, Crawford F, Kappler JW, Marrack P. Memory CD4 T cells that express CXCR5 provide accelerated help to B cells. J Immunol (Baltimore, Md: 1950). 2011;186:2889-96.
131. Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A, et al. ICOS deficiency is associated with a severe reduction of CXCR5 + CD4 germinal center Th cells. J Immunol (Baltimore, Md: 1950). 2006;177:4927-32.
132. Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, et al. Human Circulating PD-1CXCR3CXCR5 memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39:758-69.
133. Pallikkuth S, Fischl MA, Pahwa S. Combination antiretroviral therapy with raltegravir leads to rapid immunologic reconstitution in treatment-naive patients with chronic HIV infection. J Infect Dis. 2013;208:1613-23.
134. Pallikkuth S, Kanthikeel SP, Silva SY, Fischl M, Pahwa R, Pahwa S. Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients. J Allergy Clin Immunol. 2011;128:1279-85.
135. Pallikkuth S, Pilakka Kanthikeel S, Silva SY, Fischl M, Pahwa R, Pahwa S. Upregulation of IL-21 receptor on B cells and IL-21 secretion distinguishes novel 2009 H1N1 vaccine responders from nonresponders among HIV-infected persons on combination antiretroviral therapy. J Immunol (Baltimore, Md: 1950). 2011;186:6173-81.
136. Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, et al. Induction of ICOS + CXCR3 + CXCR5 + TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med. 2013;5:176ra32.
137. Reber AJ, Chirkova T, Kim JH, Cao W, Biber R, Shay DK, et al. Immunosenescence and challenges of vaccination against influenza in the aging population. Aging Dis. 3:68-90.
138. Deeks SG, Verdin E, McCune JM. Immunosenescence and HIV. Curr Opin Immunol.2012;24:501-6.
139. The Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008;372:293-9.
140. High KP, Brennan-Ing M, Clifford DB, Cohen MH, Currier J, Deeks SG, et al. HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS research by the HIV and aging working group. J Acquir Immune Defic Syndr.60(Suppl 1):S1-18.
141. Alcaide ML, Parmigiani A, Pallikkuth S, Roach M, Freguja R, Della Negra M, et al. Immune activation in HIV-infected aging women on antiretrovirals- implications for age-associated comorbidities: a cross-sectional pilot study. PloS one. 2013;8:e63804.
142. Parmigiani A, Alcaide ML, Freguja R, Pallikkuth S, Frasca D, Fischl MA, et al. Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation. PloS one. 2013 (In Press).
143. Xu Y, Weatherall C, Bailey M, Alcantara S, De Rose R, Estaquier J, et al. Simian immunodeficiency virus infects follicular helper CD4 T cells in lymphoid tissues during pathogenic infection of pigtail macaques. J Virol. 2013;87:3760-73.
144. Klatt NR, Vinton CL, Lynch RM, Canary LA, Ho J, Darrah PA, et al. SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination. Blood.118:5803-12.
145. Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R, Haddad EK, et al. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med. 2013;210:143-56.
146. Hong JJ, Amancha PK, Rogers K, Ansari AA, Villinger F. Spatial alterations between CD4(+) T follicular helper, B, and CD8(+) T cells during simian immunodeficiency virus infection: T/B cell homeostasis, activation, and potential mechanism for viral escape. J Immunol (Baltimore, Md: 1950). 2012;188:3247-56.
147. Cohen J. HIV/AIDS research. Tissue says blood is misleading, confusing HIV cure efforts. Science (New York, NY). 2011;334:1614.
148. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893-900.
149. Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang ZE, Avanesyan L, et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Investig.121:1154-62.
150. Ma SW, Huang X, Li YY, Tang LB, Sun XF, Jiang XT, et al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. J Hepatol.56:775-81.