Molecular signatures of T-cell inhibition in HIV-1 infection

Retrovirology

Adeeba Kamarulzaman⁵  Vijayakumar Velu²  Muttiah Barathan¹  Rada Ellegård³  Alireza Saeidi¹  Karlhans F Che⁴  Esaki M Shankar¹  Marie Larsson³ 

[1] Tropical Infectious Disease Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia;Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA;Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, 58 185, Sweden;Institute for Environmental Medicine, Karolinska Institute, Solna, Stockholm, 17 177, Sweden;Centre of Excellence for Research in AIDS (CERiA), Department of Medicine, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia

关键词: CD160;    2B4;    TIM-3;    PD-1;    LAG-3;    T-cell inhibition;    HIV-1;    FoxP3;    CTLA-4;    BLIMP-1;   

Others  :  1209149
DOI  :  10.1186/1742-4690-10-31

 received in 2013-01-13, accepted in 2013-03-07,  发布年份 2013

【 摘 要 】

Cellular immune responses play a crucial role in the control of viral replication in HIV-infected individuals. However, the virus succeeds in exploiting the immune system to its advantage and therefore, the host ultimately fails to control the virus leading to development of terminal AIDS. The virus adopts numerous evasion mechanisms to hijack the host immune system. We and others recently described the expression of inhibitory molecules on T cells as a contributing factor for suboptimal T-cell responses in HIV infection both in vitro and in vivo. The expression of these molecules that negatively impacts the normal functions of the host immune armory and the underlying signaling pathways associated with their enhanced expression need to be discussed. Targets to restrain the expression of these molecular markers of immune inhibition is likely to contribute to development of therapeutic interventions that augment the functionality of host immune cells leading to improved immune control of HIV infection. In this review, we focus on the functions of inhibitory molecules that are expressed or secreted following HIV infection such as BTLA, CTLA-4, CD160, IDO, KLRG1, LAG-3, LILRB1, PD-1, TRAIL, TIM-3, and regulatory cytokines, and highlight their significance in immune inhibition. We also highlight the ensemble of transcriptional factors such as BATF, BLIMP-1/PRDM1, FoxP3, DTX1 and molecular pathways that facilitate the recruitment and differentiation of suppressor T cells in response to HIV infection.

【 授权许可】

   
2013 Larsson et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Boliar S, Murphy MK, Tran TC, Carnathan DG, Armstrong WS, Silvestri G, Derdeyn CA: B-lymphocyte dysfunction in chronic HIV-1 infection does not prevent cross-clade neutralization breadth. J Virol 2012, 86:8031-8040.
• [2]Shankar EM, Che KF, Messmer D, Lifson JD, Larsson M: Expression of a broad array of negative costimulatory molecules and Blimp-1 in T cells following priming by HIV-1 pulsed dendritic cells. Mol Med 2011, 17:229-240.
• [3]Che KF, Sabado RL, Shankar EM, Tjomsland V, Messmer D, Bhardwaj N, Lifson JD, Larsson M: HIV-1 impairs in vitro priming of naive T cells and gives rise to contact-dependent suppressor T cells. Eur J Immunol 2010, 40:2248-2258.
• [4]Che KF, Shankar EM, Muthu S, Zandi S, Sigvardsson M, Hinkula J, Messmer D, Larsson M: p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 pathway signaling regulates expression of inhibitory molecules in T cells activated by HIV-1-exposed dendritic cells. Mol Med 2012, 18:1169-1182.
• [5]Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y: Human immunodeficiency virus-driven expansion of CD4 + CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 2004, 104:3249-3256.
• [6]Mojumdar K, Vajpayee M, Chauhan NK, Singh A, Singh R, Kurapati S: Loss of CD127 and increased immunosenescence of T cell subsets in HIV infected individuals. Indian J Med Res 2011, 134:972-981.
• [7]Murooka TT, Deruaz M, Marangoni F, Vrbanac VD, Seung E, von Andrian UH, Tager AM, Luster AD, Mempel TR: HIV-infected T cells are migratory vehicles for viral dissemination. Nature 2012, 490:283-287.
• [8]Migueles SA, Weeks KA, Nou E, Berkley AM, Rood JE, Osborne CM, Hallahan CW, Cogliano-Shutta NA, Metcalf JA, McLaughlin M: Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol 2009, 83:11876-11889.
• [9]Shankar EM, Solomon SS, Vignesh R, Murugavel KG, Sundaram M, Solomon S, Balakrishnan P, Kumarasamy N: GB virus infection: a silent anti-HIV panacea within? Trans R Soc Trop Med Hyg 2008, 102:1176-1180.
• [10]Riley JL, Schlienger K, Blair PJ, Carreno B, Craighead N, Kim D, Carroll RG, June CH: Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule. J Exp Med 2000, 191:1987-1997.
• [11]Wilkinson J, Cunningham AL: Mucosal transmission of HIV-1: first stop dendritic cells. Curr Drug Targets 2006, 7:1563-1569.
• [12]von Andrian UH, Mempel TR: Homing and cellular traffic in lymph nodes. Nat Rev Immunol 2003, 3:867-878.
• [13]Leitner J, Grabmeier-Pfistershammer K, Steinberger P: Receptors and ligands implicated in human T cell costimulatory processes. Immunol Lett 2010, 128:89-97.
• [14]Bertram EM, Dawicki W, Sedgmen B, Bramson JL, Lynch DH, Watts TH: A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T cell response to influenza in vivo. J Immunol 2004, 172:981-988.
• [15]Coyle AJ, Gutierrez-Ramos JC: The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function. Nat Immunol 2001, 2:203-209.
• [16]Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004, 4:336-347.
• [17]Greenwald RJ, Freeman GJ, Sharpe AH: The B7 family revisited. Annu Rev Immunol 2005, 23:515-548.
• [18]Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL: CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005, 25:9543-9553.
• [19]Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH: Reinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand blockade. J Exp Med 2006, 203:2223-2227.
• [20]Okazaki T, Honjo T: The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 2006, 27:195-201.
• [21]Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ: Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003, 170:1257-1266.
• [22]Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006, 439:682-687.
• [23]Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006, 443:350-354.
• [24]Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS: Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 2006, 12:1198-1202.
• [25]Wang X, Zhang Z, Zhang S, Fu J, Yao J, Jiao Y, Wu H, Wang FS: B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infection. Eur J Immunol 2008, 38:3226-3236.
• [26]Frebel H, Nindl V, Schuepbach RA, Braunschweiler T, Richter K, Vogel J, Wagner CA, Loffing-Cueni D, Kurrer M, Ludewig B, Oxenius A: Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. J Exp Med 2012, 17:2485-2499.
• [27]Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ: Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2009, 458:206-210.
• [28]Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, Koup RA: PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 2006, 203:2281-2292.
• [29]Peretz Y, He Z, Shi Y, Yassine-Diab B, Goulet JP, Bordi R, Filali-Mouhim A, Loubert JB, El-Far M, Dupuy FP: CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathog 2012, 8:e1002840.
• [30]Muthumani K, Choo AY, Shedlock DJ, Laddy DJ, Sundaram SG, Hirao L, Wu L, Thieu KP, Chung CW, Lankaraman KM: Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J Virol 2008, 82:11536-11544.
• [31]Oestreich KJ, Yoon H, Ahmed R, Boss JM: NFATc1 regulates PD-1 expression upon T cell activation. J Immunol 2008, 181:4832-4839.
• [32]Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA, Fauci AS: The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008, 181:6738-6746.
• [33]Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, Julg B, Jesneck JL, Brosnahan K, Imam S: Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 2010, 16:1147-1151.
• [34]Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA: B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000, 12:431-440.
• [35]Read S, Malmstrom V, Powrie F: Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000, 192:295-302.
• [36]Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S: CTLA-4 control over FoxP3+ regulatory T cell function. Science 2008, 322:271-275.
• [37]Leng Q, Bentwich Z, Magen E, Kalinkovich A, Borkow G: CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention. AIDS 2002, 16:519-529.
• [38]Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A: Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 2007, 8:1246-1254.
• [39]Kaufmann DE, Walker BD: PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol 2009, 182:5891-5897.
• [40]Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P: CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002, 3:1097-1101.
• [41]Kuchroo VK, Dardalhon V, Xiao S, Anderson AC: New roles for TIM family members in immune regulation. Nat Rev Immunol 2008, 8:577-580.
• [42]Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ: The TIM gene family: emerging roles in immunity and disease. Nat Rev Immunol 2003, 3:454-462.
• [43]Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA: Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002, 415:536-541.
• [44]Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK: Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol 2011, 32:345-349.
• [45]Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S: Identification of Tim4 as a phosphatidylserine receptor. Nature 2007, 450:435-439.
• [46]Chou FC, Shieh SJ, Sytwu HK: Attenuation of Th1 response through galectin-9 and T-cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice. Eur J Immunol 2009, 39:2403-2411.
• [47]Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, Cornejo M, Nishi N, Yamauchi A, Quintana FJ: Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b + Ly-6G + myeloid cells. J Immunol 2010, 185:1383-1392.
• [48]Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, Yue FY, Gyenes G, Wong D, Klein MB, Saeed S: HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol 2010, 40:2493-2505.
• [49]Sakhdari A, Mujib S, Vali B, Yue FY, MacParland S, Clayton K, Jones RB, Liu J, Lee EY, Benko E: Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection. PLoS One 2012, 7:e40146.
• [50]Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM: Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 2008, 205:2763-2779.
• [51]Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah AJ, Goedert JJ, Winkler C, O’Brien SJ, Rinaldo C: Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996, 2:405-411.
• [52]Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O’Brien SJ: HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999, 283:1748-1752.
• [53]Elahi S, Dinges WL, Lejarcegui N, Laing KJ, Collier AC, Koelle DM, McElrath MJ, Horton H: Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat Med 2011, 17:989-995.
• [54]Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, Van Baarle D, Kostense S, Miedema F, McLaughlin M: HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002, 3:1061-1068.
• [55]Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR: Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 2009, 83:9122-9130.
• [56]McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M, Allen TM, Gretch DR, Rosen HR: Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest 2010, 120:4546-4557.
• [57]Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, Freeman GJ, Kuchroo VK, Ahmed R: Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 2010, 107:14733-14738.
• [58]Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, Hartmann D, Black RA, Rossi JJ, Blobel CP: Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J 2007, 26:494-504.
• [59]Price P, Keane N, Gray L, Lee S, Gorry PR, French MA: CXCR4 or CCR5 tropism of human immunodeficiency virus type 1 isolates does not determine the immunological milieu in patients responding to antiretroviral therapy. Viral Immunol 2006, 19:734-740.
• [60]Hannier S, Tournier M, Bismuth G, Triebel F: CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol 1998, 161:4058-4065.
• [61]Okazaki T, Okazaki I, Wang J, Sugiura D, Nakaki F, Yoshida T, Kato Y, Fagarasan S, Muramatsu M, Eto T, Hioki K, Honjo T: PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med 2011, 208:395-407.
• [62]Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA: Role of LAG-3 in regulatory T cells. Immunity 2004, 21:503-513.
• [63]Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ: Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009, 10:29-37.
• [64]Giustiniani J, Bensussan A, Marie-Cardine A: Identification and characterization of a transmembrane isoform of CD160 (CD160-TM), a unique activating receptor selectively expressed upon human NK cell activation. J Immunol 2009, 182:63-71.
• [65]Richter K, Agnellini P, Oxenius A: On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int Immunol 2010, 22:13-23.
• [66]del Rio ML, Lucas CL, Buhler L, Rayat G, Rodriguez-Barbosa JI: HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation. J Leukoc Biol 2010, 87:223-235.
• [67]Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ: CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol 2008, 9:176-185.
• [68]Abecassis S, Giustiniani J, Meyer N, Schiavon V, Ortonne N, Campillo JA, Bagot M, Bensussan A: Identification of a novel CD160+ CD4+ T-lymphocyte subset in the skin: a possible role for CD160 in skin inflammation. J Invest Dermatol 2007, 127:1161-1166.
• [69]Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL, Murphy KM: B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 2005, 6:90-98.
• [70]Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X: BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 2003, 4:670-679.
• [71]Li Q, Smith AJ, Schacker TW, Carlis JV, Duan L, Reilly CS, Haase AT: Microarray analysis of lymphatic tissue reveals stage-specific, gene expression signatures in HIV-1 infection. J Immunol 2009, 183:1975-1982.
• [72]Vendel AC, Calemine-Fenaux J, Izrael-Tomasevic A, Chauhan V, Arnott D, Eaton DL: B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK. J Immunol 2009, 182:1509-1517.
• [73]Zhang Z, Xu X, Lu J, Zhang S, Gu L, Fu J, Jin L, Li H, Zhao M, Zhang J: B and T lymphocyte attenuator down-regulation by HIV-1 depends on type I interferon and contributes to T-cell hyperactivation. J Infect Dis 2011, 203:1668-1678.
• [74]Xu XS, Zhang Z, Gu LL, Wang FS: BTLA Characterization and its association with disease progression in patients with chronic HIV-1 infection. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2009, 25:1158-1160.
• [75]Mathew SO, Vaidya SV, Kim JR, Mathew PA: Human natural killer cell receptor 2B4 (CD244) down-regulates its own expression by reduced promoter activity at an Ets element. Biochem Biophys Res Commun 2007, 355:483-487.
• [76]Schlaphoff V, Lunemann S, Suneetha PV, Jaroszewicz J, Grabowski J, Dietz J, Helfritz F, Bektas H, Sarrazin C, Manns MP: Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLoS Pathog 2011, 7:e1002045.
• [77]Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R: Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 2010, 6:e1000947.
• [78]Kumar V, McNerney ME: A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nat Rev Immunol 2005, 5:363-374.
• [79]Ostrowski SR, Ullum H, Pedersen BK, Gerstoft J, Katzenstein TL: 2B4 expression on natural killer cells increases in HIV-1 infected patients followed prospectively during highly active antiretroviral therapy. Clin Exp Immunol 2005, 141:526-533.
• [80]Peritt D, Sesok-Pizzini DA, Schretzenmair R, Macgregor RR, Valiante NM, Tu X, Trinchieri G, Kamoun M: C1.7 antigen expression on CD8+ T cells is activation dependent: increased proportion of C1.7 + CD8+ T cells in HIV-1-infected patients with progressing disease. J Immunol 1999, 162:7563-7568.
• [81]Aldy KN, Horton NC, Mathew PA, Mathew SO: 2B4+ CD8+ T cells play an inhibitory role against constrained HIV epitopes. Biochem Biophys Res Commun 2011, 405:503-507.
• [82]Yamamoto T, Price DA, Casazza JP, Ferrari G, Nason M, Chattopadhyay PK, Roederer M, Gostick E, Katsikis PD, Douek DC: Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection. Blood 2011, 117:4805-4815.
• [83]McIntire RH, Sifers T, Platt JS, Ganacias KG, Langat DK, Hunt JS: Novel HLA-G-binding leukocyte immunoglobulin-like receptor (LILR) expression patterns in human placentas and umbilical cords. Placenta 2008, 29:631-638.
• [84]Anderson KJ, Allen RL: Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells. Immunology 2009, 127:8-17.
• [85]Lichterfeld M, Kavanagh DG, Williams KL, Moza B, Mui SK, Miura T, Sivamurthy R, Allgaier R, Pereyra F, Trocha A: A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells. J Exp Med 2007, 204:2813-2824.
• [86]O’Connor GM, Holmes A, Mulcahy F, Gardiner CM: Natural Killer cells from long-term non-progressor HIV patients are characterized by altered phenotype and function. Clin Immunol 2007, 124:277-283.
• [87]Anfossi N, Doisne JM, Peyrat MA, Ugolini S, Bonnaud O, Bossy D, Pitard V, Merville P, Moreau JF, Delfraissy JF: Coordinated expression of Ig-like inhibitory MHC class I receptors and acquisition of cytotoxic function in human CD8+ T cells. J Immunol 2004, 173:7223-7229.
• [88]Vlad G, Piazza F, Colovai A, Cortesini R, Della Pietra F, Suciu-Foca N, Manavalan JS: Interleukin-10 induces the upregulation of the inhibitory receptor ILT4 in monocytes from HIV positive individuals. Hum Immunol 2003, 64:483-489.
• [89]Huang J, Burke PS, Cung TD, Pereyra F, Toth I, Walker BD, Borges L, Lichterfeld M, Yu XG: Leukocyte immunoglobulin-like receptors maintain unique antigen-presenting properties of circulating myeloid dendritic cells in HIV-1-infected elite controllers. J Virol 2010, 84:9463-9471.
• [90]Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C, Dolan MJ, Yagita H, Lifson JD, Shearer GM: CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood 2005, 106:3524-3531.
• [91]Vidalain PO, Azocar O, Lamouille B, Astier A, Rabourdin-Combe C, Servet-Delprat C: Measles virus induces functional TRAIL production by human dendritic cells. J Virol 2000, 74:556-559.
• [92]Lunemann JD, Waiczies S, Ehrlich S, Wendling U, Seeger B, Kamradt T, Zipp F: Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells. J Immunol 2002, 168:4881-4888.
• [93]Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM: The receptor for the cytotoxic ligand TRAIL. Science 1997, 276:111-113.
• [94]Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L: Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 1997, 7:821-830.
• [95]Voehringer D, Blaser C, Brawand P, Raulet DH, Hanke T, Pircher H: Viral infections induce abundant numbers of senescent CD8 T cells. J Immunol 2001, 167:4838-4843.
• [96]Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop AD, Rickinson AB, Rowland-Jones SL, Blum HE, Pircher H: Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. J Virol 2005, 79:12112-12116.
• [97]Gründemann C, Schwartzkopff S, Koschella M, Schweier O, Peters C, Voehringer D, Pircher H: The NK receptor KLRG1 is dispensable for virus-induced NK and CD8+ T-cell differentiation and function in vivo. Eur J Immunol 2010, 40:1303-1314.
• [98]Martins G, Calame K: Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol 2008, 26:133-169.
• [99]Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Meffre E, Jacob J, Calame K, Kaech SM: Transcriptional repressor BLIMP-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 2009, 31:296-308.
• [100]Kallies A, Hawkins ED, Belz GT, Metcalf D, Hommel M, Corcoran LM, Hodgkin PD, Nutt SL: Transcriptional repressor BLIMP-1 is essential for T cell homeostasis and self-tolerance. Nat Immunol 2006, 7:466-474.
• [101]Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY: Genome-wide analysis of FoxP3 target genes in developing and mature regulatory T cells. Nature 2007, 445:936-940.
• [102]Ohkura N, Sakaguchi S: Maturation of effector regulatory T cells. Nat Immunol 2011, 12:283-284.
• [103]Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL, Wherry EJ: A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity 2009, 31:309-320.
• [104]Seddiki N, Phetsouphanh C, Swaminathan S, Xu Y, Rao S, Li J, Sutcliffe EL, Denyer G, Finlayson R, Gelgor L, Cooper DA, Zaunders J, Kelleher AD: The microRNA-9/B-lymphocyte-induced maturation protein-1/IL-2 axis is differentially regulated in progressive HIV infection. Eur J Immunol 2013, 43:510-520.
• [105]Thaventhiran JE, Fearon DT: Control of HIV infection: Escape from the shadow of Blimp-1. Eur J Immunol 2013, 43:323-326.
• [106]Nigam P, Velu V, Kannanganat S, Chennareddi L, Kwa S, Siddiqui M, Amara RR: Expansion of FOXP3+ CD8 T cells with suppressive potential in colorectal mucosa following a pathogenic simian immunodeficiency virus infection correlates with diminished antiviral T cell response and viral control. J Immunol 2010, 184:1690-1701.
• [107]Nilsson J, Boasso A, Velilla PA, Zhang R, Vaccari M, Franchini G, Shearer GM, Andersson J, Chougnet C: HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 2006, 108:3808-3817.
• [108]Andersson J, Boasso A, Nilsson J, Zhang R, Shire NJ, Lindback S, Shearer GM, Chougnet CA: The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. J Immunol 2005, 174:3143-3147.
• [109]Aandahl EM, Michaelsson J, Moretto WJ, Hecht FM, Nixon DF: Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J Virol 2004, 78:2454-2459.
• [110]Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, Planta M, McGlaughlin M, Jackson R, Ziegler SF, Fauci AS: CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med 2004, 200:331-343.
• [111]Birebent B, Lorho R, Lechartier H, de Guibert S, Alizadeh M, Vu N, Beauplet A, Robillard N, Semana G: Suppressive properties of human CD4 + CD25+ regulatory T cells are dependent on CTLA-4 expression. Eur J Immunol 2004, 34:3485-3496.
• [112]Loxton A, Roberts T, Black G, Walzl G: P16–01. Regulatory T-cells and high levels of FOXP3 mRNA leads to decreased immune responses in HIV-TB co-infection. Retrovirology 2009, 6:P230.
• [113]Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF: FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006, 126:375-387.
• [114]Hersperger AR, Martin JN, Shin LY, Sheth PM, Kovacs CM, Cosma GL, Makedonas G, Pereyra F, Walker BD, Kaul R: Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. Blood 2011, 117:3799-3808.
• [115]Townsend MJ, Weinmann AS, Matsuda JL, Salomon R, Farnham PJ, Biron CA, Gapin L, Glimcher LH: T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity 2004, 20:477-494.
• [116]Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, Mullen AC, Gasink CR, Kaech SM, Miller JD: Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 2005, 6:1236-1244.
• [117]Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, Intlekofer AM, Boss JM, Reiner SL, Weinmann AS, Wherry EJ: Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 2011, 12:663-671.
• [118]Oestreich KJ, Weinmann AS: T-bet employs diverse regulatory mechanisms to repress transcription. Trends Immunol 2012, 33:78-83.
• [119]Kallies A, Carotta S, Huntington ND, Bernard NJ, Tarlinton DM, Smyth MJ, Nutt SL: A role for Blimp1 in the transcriptional network controlling natural killer cell maturation. Blood 2011, 117:1869-1879.
• [120]Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM: Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 2007, 27:281-295.
• [121]Thaventhiran JE, Hoffmann A, Magiera L, de la Roche M, Lingel H, Brunner-Weinzierl M, Fearon DT: Activation of the Hippo pathway by CTLA-4 regulates the expression of BLIMP-1 in the CD8+ T cell. Proc Natl Acad Sci U S A 2012, 109:2223-2229.
• [122]Williams KL, Nanda I, Lyons GE, Kuo CT, Schmid M, Leiden JM, Kaplan MH, Taparowsky EJ: Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus. Eur J Immunol 2001, 31:1620-1627.
• [123]Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995, 3:673-682.
• [124]Kuroda S, Yamazaki M, Abe M, Sakimura K, Takayanagi H, Iwai Y: Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression. Proc Natl Acad Sci U S A 2011, 108:14885-14889.
• [125]Schraml BU, Hildner K, Ise W, Lee WL, Smith WA, Solomon B, Sahota G, Sim J, Mukasa R, Cemerski S, Hatton RD, Stormo GD, Weaver CT, Russell JH, Murphy TL, Murphy KM: The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 2009, 460:405-409.
• [126]Lim CP, Cao X: Regulation of Stat3 activation by MEK kinase 1. J Biol Chem 2001, 276:21004-21011.
• [127]Zarubin T, Han J: Activation and signaling of the p38 MAP kinase pathway. Cell Res 2005, 15:11-18.
• [128]Gibson HM, Hedgcock CJ, Aufiero BM, Wilson AJ, Hafner MS, Tsokos GC, Wong HK: Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter. J Immunol 2007, 179:3831-3840.
• [129]Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A: Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc Natl Acad Sci U S A 2007, 104:4565-4570.
• [130]Migueles SA, Osborne CM, Royce C, Compton AA, Joshi RP, Weeks KA, Rood JE, Berkley AM, Sacha JB, Cogliano-Shutta NA: Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 2008, 29:1009-1021.
• [131]Hsiao HW, Liu WH, Wang CJ, Lo YH, Wu YH, Jiang ST, Lai MZ: Deltex1 is a target of the transcription factor NFAT that promotes T cell anergy. Immunity 2009, 31:72-83.
• [132]Sakoe Y, Sakoe K, Kirito K, Ozawa K, Komatsu N: FOXO3A as a key molecule for all-trans retinoic acid-induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia. Blood 2010, 115:3787-3795.
• [133]Dabrowska A, Kim N, Aldovini A: Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes. J Immunol 2008, 181:8460-8477.
• [134]van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, Peretz Y, Filali-Mouhim A, Dupuy FP, Procopio FA, Chomont N, Balderas RS, Said EA, Boulassel MR, Tremblay CL, Routy JP, Sékaly RP, Haddad EK: Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis. J Clin Invest 2011, 121:3877-3888.
• [135]Kleinsteuber K, Heesch K, Schattling S, Sander-Juelch C, Mock U, Riecken K, Fehse B, Fleischer B, Jacobsen M: SOCS3 promotes interleukin-17 expression of human T cells. Blood 2012, 120:4374-4382.
• [136]Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR, Shahinian A, Lang PA, Lang KS, Morre M: IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 2011, 144:601-613.
• [137]Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D: Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007, 130:1120-1133.
• [138]Moffett JR, Namboodiri MA: Tryptophan and the immune response. Immunol Cell Biol 2003, 81:247-265.
• [139]Mellor AL, Munn DH: IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004, 4:762-774.
• [140]Baban B, Hansen AM, Chandler PR, Manlapat A, Bingaman A, Kahler DJ, Munn DH, Mellor AL: A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation. Int Immunol 2005, 17:909-919.
• [141]Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P: Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003, 4:1206-1212.
• [142]Mulley WR, Nikolic-Paterson DJ: Indoleamine 2,3-dioxygenase in transplantation. Nephrology (Carlton) 2008, 13:204-211.
• [143]Werner ER, Fuchs D, Hausen A, Jaeger H, Reibnegger G, Werner-Felmayer G, Dierich MP, Wachter H: Tryptophan degradation in patients infected by human immunodeficiency virus. Biol Chem Hoppe Seyler 1988, 369:337-340.
• [144]Boasso A, Shearer GM: How does indoleamine 2,3-dioxygenase contribute to HIV-mediated immune dysregulation. Curr Drug Metab 2007, 8:217-223.
• [145]Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, Servillo G, Brunacci C, Calvitti M, Bicciato S: Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol 2011, 12:870-878.
• [146]Moore KW, de Waal MR, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001, 19:683-765.
• [147]Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB: Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 2004, 22:929-979.
• [148]Jin HT, Jeong YH, Park HJ, Ha SJ: Mechanism of T cell exhaustion in a chronic environment. BMB Rep 2011, 44:217-231.
• [149]Brooks DG, Ha SJ, Elsaesser H, Sharpe AH, Freeman GJ, Oldstone MB: IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci U S A 2008, 105:20428-20433.
• [150]Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP: Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 2010, 16:452-459.
• [151]Stylianou E, Aukrust P, Kvale D, Muller F, Froland SS: IL-10 in HIV infection: increasing serum IL-10 levels with disease progression-down-regulatory effect of potent anti-retroviral therapy. Clin Exp Immunol 1999, 116:115-120.
• [152]Clerici M, Wynn TA, Berzofsky JA, Blatt SP, Hendrix CW, Sher A, Coffman RL, Shearer GM: Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest 1994, 93:768-775.
• [153]Brockman MA, Kwon DS, Tighe DP, Pavlik DF, Rosato PC, Sela J, Porichis F, Le Gall S, Waring MT, Moss K: IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 2009, 114:346-356.
• [154]Li MO, Sanjabi S, Flavell RA: Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 2006, 25:455-471.
• [155]Elrefaei M, Burke CM, Baker CA, Jones NG, Bousheri S, Bangsberg DR, Cao H: TGF-β and IL-10 production by HIV-specific CD8+ T cells is regulated by CTLA-4 signaling on CD4+ T cells. PLoS One 2009, 4:e8194.
• [156]Elrefaei M, Burke CM, Baker CAR, Jones NG, Bousheri S, Bangsberg DR, Cao H: HIV-specific TGF-β-positive CD4+ T cells do not express regulatory surface markers and are regulated by CTLA-4. AIDS Res Hum Retroviruses 2010, 26:329-337.
• [157]Garidou L, Heydari S, Gossa S, McGavern DB: Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection. J Virol 2012, 86:7060-7071.
• [158]Boettler T, Cheng Y, Ehrhardt K, von Herrath M: TGF-β blockade does not improve control of an established persistent viral infection. Viral Immunol 2012, 25:232-238.
• [159]Khaitan A, Unutmaz D: Revisiting immune exhaustion during HIV infection. Curr HIV/AIDS Rep 2011, 8:4-11.