Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection

Retrovirology

Marylyn M Addo¹  Marcus Altfeld²  Alicja Piechocka-Trocha¹  Ildiko Toth¹  Jeff Reardon¹  Keith Rands¹  Wilfredo F Garcia-Beltran¹  Uriel Y Moreno-Nieves¹  Stephanie Jost¹ 

[1] Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA;Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany

关键词: NK cells;    Innate immunity;    HIV-1;    Gal-9;    Tim-3;   

Others  :  1209101
DOI  :  10.1186/1742-4690-10-74

 received in 2013-02-22, accepted in 2013-06-13,  发布年份 2013

【 摘 要 】

Background

Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.

Results

We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.

Conclusions

Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

【 授权许可】

   
2013 Jost et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]2012 UNAIDS Report on the Global AIDS Epidemic [http:/ / www.unaids.org/ en/ media/ unaids/ contentassets/ documents/ epidemiology/ 2012/ gr2012/ 20121120_UNAIDS_Global_Report_2012_ en.pdf] webcite
• [2]Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, Trowsdale J, et al.: Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002, 31:429-434.
• [3]Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, Colombo S, Brown EE, Shupert WL, Phair J, et al.: Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 2007, 39:733-740.
• [4]Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A, Streeck H, Waring M, Meier A, Brander C, et al.: Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 2007, 204:3027-3036.
• [5]Alter G, Rihn S, Walter K, Nolting A, Martin M, Rosenberg ES, Miller JS, Carrington M, Altfeld M: HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection. J Virol 2009, 83:6798-6805.
• [6]Boulet S, Kleyman M, Kim JY, Kamya P, Sharafi S, Simic N, Bruneau J, Routy JP, Tsoukas CM, Bernard NF: A combined genotype of KIR3DL1 high expressing alleles and HLA-B*57 is associated with a reduced risk of HIV infection. AIDS 2008, 22:1487-1491.
• [7]Boulet S, Sharafi S, Simic N, Bruneau J, Routy JP, Tsoukas CM, Bernard NF: Increased proportion of KIR3DS1 homozygotes in HIV-exposed uninfected individuals. AIDS 2008, 22:595-599.
• [8]Boulet S, Song R, Kamya P, Bruneau J, Shoukry NH, Tsoukas CM, Bernard NF: HIV protective KIR3DL1 and HLA-B genotypes influence NK cell function following stimulation with HLA-devoid cells. J Immunol 2010, 184:2057-2064.
• [9]Parsons MS, Boulet S, Song R, Bruneau J, Shoukry NH, Routy JP, Tsoukas CM, Bernard NF: Mind the gap: lack of association between KIR3DL1*004/HLA-Bw4-induced natural killer cell function and protection from HIV infection. J Infect Dis 2010, 202(Suppl 3):S356-360.
• [10]Alter G, Heckerman D, Schneidewind A, Fadda L, Kadie CM, Carlson JM, Oniangue-Ndza C, Martin M, Li B, Khakoo SI, et al.: HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 2011, 476:96-100.
• [11]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 2008, 22:1551-1560.
• [12]O'Connell KA, Han Y, Williams TM, Siliciano RF, Blankson JN: Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. J Virol 2009, 83:5028-5034.
• [13]Paust S, von Andrian UH: Natural killer cell memory. Nat Immunol 2011, 12:500-508.
• [14]Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, Voigt V, Fleming P, Tabarias H, Hill GR, van der Most RG, et al.: Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 2010, 207:1333-1343.
• [15]Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA: NK cell and DC interactions. Trends Immunol 2004, 25:47-52.
• [16]Robbins SH, Bessou G, Cornillon A, Zucchini N, Rupp B, Ruzsics Z, Sacher T, Tomasello E, Vivier E, Koszinowski UH, Dalod M: Natural killer cells promote early CD8 T cell responses against cytomegalovirus. PLoS Pathog 2007, 3:e123.
• [17]Waggoner SN, Cornberg M, Selin LK, Welsh RM: Natural killer cells act as rheostats modulating antiviral T cells. Nature 2012, 481:394-398.
• [18]Lanier LL: NK cell recognition. Annu Rev Immunol 2005, 23:225-274.
• [19]Khademi M, Illes Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, et al.: T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 2004, 172:7169-7176.
• [20]Gleason MK, Lenvik TR, McCullar V, Felices M, O'Brien MS, Cooley SA, Verneris MR, Cichocki F, Holman CJ, Panoskaltsis-Mortari A, et al.: Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood 2012, 119:3064-3072.
• [21]Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL: Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 2012, 119:3734-3743.
• [22]Zhu C, Anderson AC, Kuchroo VK: TIM-3 and its regulatory role in immune responses. Curr Top Microbiol Immunol 2011, 350:1-15.
• [23]Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, et al.: Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002, 415:536-541.
• [24]Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W: Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2012, 56:1342-1351.
• [25]Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM, et al.: 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.
• [26]Sakhdari A, Mujib S, Vali B, Yue FY, Macparland S, Clayton K, Jones RB, Liu J, Lee EY, Benko E, et al.: Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8(+) T Cells in HIV Infection. PLoS One 2012, 7:e40146.
• [27]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.
• [28]Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, Yue FY, Gyenes G, Wong D, Klein MB, Saeed S, et al.: 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.
• [29]Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK: The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005, 6:1245-1252.
• [30]DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, et al.: T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 2010, 184:1918-1930.
• [31]Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K: Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 2009, 113:3821-3830.
• [32]Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, et al.: Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 2012, 13:832-842.
• [33]Wada J, Kanwar YS: Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J Biol Chem 1997, 272:6078-6086.
• [34]Bi S, Earl LA, Jacobs L, Baum LG: Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem 2008, 283:12248-12258.
• [35]Elahi S, Niki T, Hirashima M, Horton H: Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection. Blood 2012, 119:4192-4204.
• [36]Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, et al.: Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 2007, 318:1141-1143.
• [37]Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK: Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 2003, 4:1102-1110.
• [38]Bi S, Hong PW, Lee B, Baum LG: Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci USA 2011, 108:10650-10655.
• [39]Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Fedorov A, Fedorov E, Zencheck WD, Lary JW, Cole JL, Deng H, et al.: T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity 2007, 26:311-321.
• [40]Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, Liu Y, Zhu F, Zhang L, Sun W, et al.: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 2010, 52:322-329.
• [41]Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT, Streeck H, Johnston MN, Staller KD, Zaman MT, et al.: Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood 2005, 106:3366-3369.
• [42]Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, O'Shea MA, Kinter A, Kovacs C, Moretta A, Fauci AS: Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA 2005, 102:2886-2891.
• [43]Gay C, Dibben O, Anderson JA, Stacey A, Mayo AJ, Norris PJ, Kuruc JD, Salazar-Gonzalez JF, Li H, Keele BF, et al.: Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy. PLoS One 2011, 6:e19617.
• [44]Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, Lebedeva M, DeCamp A, Li D, Grove D, et al.: Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 2009, 83:3719-3733.
• [45]Finney CA, Ayi K, Wasmuth JD, Sheth PM, Kaul R, Loutfy M, Kain KC, Serghides L: HIV Infection Deregulates Tim-3 Expression on Innate Cells; Combination Antiretroviral Therapy Results in Partial Restoration. J Acquir Immune Defic Syndr 2013, 63:161-167.
• [46]Alter G, Jost S, Rihn S, Reyor L, Nolan B, Ghebremichael M, Bosch R, Altfeld M, Lauer G: Reduced frequencies of NKp30 + NKp46+, CD161+ and NKG2D + NK cells in acute HCV infection may predict viral clearance. J Hepatol 2010.
• [47]Lanier LL: Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008, 9:495-502.
• [48]Leitner J, Rieger A, Pickl WF, Zlabinger G, Grabmeier-Pfistershammer K, Steinberger P: TIM-3 Does Not Act as a Receptor for Galectin-9. PLoS Pathog 2013, 9:e1003253.
• [49]Chlewicki LK, Velikovsky CA, Balakrishnan V, Mariuzza RA, Kumar V: Molecular basis of the dual functions of 2B4 (CD244). J Immunol 2008, 180:8159-8167.
• [50]Golden-Mason L, McMahan RH, Strong M, Reisdorph R, Mahaffey S, Palmer BE, Cheng L, Kulesza C, Hirashima M, Niki T, Rosen HR: Galectin-9 functionally impairs natural killer (NK) cells in humans and mice. J Virol 2013, 87:4835-4845.
• [51]Alter G, Malenfant JM, Altfeld M: CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 2004, 294:15-22.