Activated platelet-T-cell conjugates in peripheral blood of patients with HIV infection: coupling coagulation/inflammation and T cells

Samantha A Green, Mindy Smith, Rebecca B Hasley, David Stephany, Adam Harned, Kunio Nagashima, Shahed Abdullah, Stefania Pittaluga, Tomozumi Imamichi, Jing Qin, Adam Rupert, Alex Ober, H Clifford Lane, Marta Catalfamo, Samantha A Green, Mindy Smith, Rebecca B Hasley, David Stephany, Adam Harned, Kunio Nagashima, Shahed Abdullah, Stefania Pittaluga, Tomozumi Imamichi, Jing Qin, Adam Rupert, Alex Ober, H Clifford Lane, Marta Catalfamo

Abstract

Background: Despite successfully suppressed viremia by treatment, patients with high levels of biomarkers of coagulation/inflammation are at an increased risk of developing non-AIDS defining serious illnesses such as cardiovascular diseases. Thus, there is a relationship between persistent immune activation and coagulation/inflammation, although the mechanisms are poorly understood. Platelets play an important role in this process. Although interactions between platelets and elements of the innate immune system, such as monocytes, are well described, little is known about the interaction between platelets and the adaptive immune system.

Design: We investigated the interaction of a component of the coagulation system, platelets, and the adaptive immune system T cells.

Methods: Healthy controls and combination antiretroviral therapy (cART)-treated HIV-infected patients with viral loads of less than 40 copies/ml for more than 15 months were analysed for platelet-T-cell conjugate formation.

Results: Platelets can form conjugates with T cells and were preferentially seen in CD4 and CD8 T-cell subsets with more differentiated phenotypes [memory, memory/effector and terminal effector memory (TEM)]. Compared with healthy controls, these conjugates in patients with HIV infection were more frequent, more often composed of activated platelets (CD42bCD62P), and were significantly associated with the D-dimer serum levels.

Conclusion: These data support a model in which platelet-T-cell conjugates may play a critical role in the fast recruitment of antigen-experienced T cells to the place of injury. This mechanism can contribute in maintaining a state of coagulation/inflammation observed in these patients contributing to the pathology of the disease.

Figures

Fig. 1
Fig. 1
Preferential binding of recombinant CD62P-Fc to CD4+ and CD8+ T-cell subsets with memory, memory/effector and TEM phenotypes.
Fig. 2
Fig. 2
Platelet–T-cell conjugates in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients and healthy controls.
Fig. 3
Fig. 3
Increased platelet–T-cell conjugates formation after thrombin stimulation in CD4+ T-cell subsets.
Fig. 4
Fig. 4
Increased platelet–T-cell conjugates after thrombin stimulation in CD8+ T-cell subsets.
Fig. 5
Fig. 5
Thrombin enhances formation of platelet–CD4+ and platelet–CD8+ T-cell conjugates.

References

    1. Catalfamo M, Di Mascio M, Hu Z, Srinivasula S, Thaker V, Adelsberger J, et al. HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells. Proc Natl Acad Sci U S A 2008; 105:19851–19856.
    1. Catalfamo M, Wilhelm C, Tcheung L, Proschan M, Friesen T, Park JH, et al. CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7. J Immunol 2011; 186:2106–2116.
    1. Lee SA, Sinclair E, Jain V, Huang Y, Epling L, Van Natta M, et al. Low proportions of CD28- CD8+ T cells expressing CD57 can be reversed by early ART initiation and predict mortality in treated HIV infection. J Infect Dis 2014; 210:374–382.
    1. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog 2014; 10:e1004078.
    1. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:83–92.
    1. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
    1. Baker JV, Neuhaus J, Duprez D, Kuller LH, Tracy R, Belloso WH, et al. Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection. J Acquir Immune Defic Syndr 2011; 56:36–43.
    1. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet 2013; 382:1525–1533.
    1. Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012; 7:e44454.
    1. Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109:2698–2704.
    1. Funderburg NT, Mayne E, Sieg SF, Asaad R, Jiang W, Kalinowska M, et al. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 2010; 115:161–167.
    1. Hurley A, Smith M, Karpova T, Hasley RB, Belkina N, Shaw S, et al. Enhanced effector function of CD8(+) T cells from healthy controls and HIV-infected patients occurs through thrombin activation of protease-activated receptor 1. J Infect Dis 2013; 207:638–650.
    1. Singh MV, Davidson DC, Kiebala M, Maggirwar SB. Detection of circulating platelet-monocyte complexes in persons infected with human immunodeficiency virus type-1. J Virol Methods 2012; 181:170–176.
    1. Holme PA, Muller F, Solum NO, Brosstad F, Froland SS, Aukrust P. Enhanced activation of platelets with abnormal release of RANTES in human immunodeficiency virus type 1 infection. FASEB J 1998; 12:79–89.
    1. Mayne E, Funderburg NT, Sieg SF, Asaad R, Kalinowska M, Rodriguez B, et al. Increased platelet and microparticle activation in HIV infection: upregulation of P-selectin and tissue factor expression. J Acquir Immune Defic Syndr 2012; 59:340–346.
    1. Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Dynamics of leukocyte-platelet adhesion in whole blood. Blood 1991; 78:1730–1737.
    1. de Bruijne-Admiraal LG, Modderman PW, Von dem Borne AE, Sonnenberg A. P-selectin mediates Ca(2+)-dependent adhesion of activated platelets to many different types of leukocytes: detection by flow cytometry. Blood 1992; 80:134–142.
    1. Zamora C, Canto E, Nieto JC, Ortiz MA, Diaz-Torne C, Diaz-Lopez C, et al. Functional consequences of platelet binding to T lymphocytes in inflammation. J Leukoc Biol 2013; 94:521–529.
    1. Li N, Ji Q, Hjemdahl P. Platelet-lymphocyte conjugation differs between lymphocyte subpopulations. J Thromb Haemost 2006; 4:874–881.
    1. Sarma J, Laan CA, Alam S, Jha A, Fox KA, Dransfield I. Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 2002; 105:2166–2171.
    1. Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104:1533–1537.
    1. Harding SA, Sommerfield AJ, Sarma J, Twomey PJ, Newby DE, Frier BM, et al. Increased CD40 ligand and platelet-monocyte aggregates in patients with type 1 diabetes mellitus. Atherosclerosis 2004; 176:321–325.
    1. Joseph JE, Harrison P, Mackie IJ, Isenberg DA, Machin SJ. Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. Br J Haematol 2001; 115:451–459.
    1. Ashman N, Macey MG, Fan SL, Azam U, Yaqoob MM. Increased platelet-monocyte aggregates and cardiovascular disease in end-stage renal failure patients. Nephrol Dial Transplant 2003; 18:2088–2096.
    1. Metcalf Pate KA, Lyons CE, Dorsey JL, Shirk EN, Queen SE, Adams RJ, et al. Platelet activation and platelet-monocyte aggregate formation contribute to decreased platelet count during acute simian immunodeficiency virus infection in pig-tailed macaques. J Infect Dis 2013; 208:874–883.
    1. Pandrea I, Cornell E, Wilson C, Ribeiro RM, Ma D, Kristoff J, et al. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood 2012; 120:1357–1366.
    1. Ley K, Kansas GS. Selectins in T-cell recruitment to nonlymphoid tissues and sites of inflammation. Nat Rev Immunol 2004; 4:325–335.
    1. Diacovo TG, Catalina MD, Siegelman MH, von Andrian UH. Circulating activated platelets reconstitute lymphocyte homing and immunity in L-selectin-deficient mice. J Exp Med 1998; 187:197–204.
    1. Michelson AD, Ellis PA, Barnard MR, Matic GB, Viles AF, Kestin AS. Downregulation of the platelet surface glycoprotein Ib-IX complex in whole blood stimulated by thrombin, adenosine diphosphate, or an in vivo wound. Blood 1991; 77:770–779.
    1. Lundgren JD, Baxter J, Deeks SG, Lane HC. Biomarkers in HIV disease. Curr Opin HIV AIDS 2010; 5:459–462.
    1. Baker JV, Neuhaus J, Duprez D, Kuller LH, Tracy R, Belloso WH, et al. Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection. J Acquir Immune Defic Syndr 2011; 56:36–43.
    1. Coppinger JA, O’Connor R, Wynne K, Flanagan M, Sullivan M, Maguire PB, et al. Moderation of the platelet releasate response by aspirin. Blood 2007; 109:4786–4792.
    1. Semple JW, Italiano JE, Jr, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11:264–274.
    1. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391:591–594.
    1. Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med 2005; 11:1167–1169.
    1. Shiraki R, Inoue N, Kawasaki S, Takei A, Kadotani M, Ohnishi Y, et al. Expression of Toll-like receptors on human platelets. Thromb Res 2004; 113:379–385.
    1. Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood 2003; 101:2661–2666.
    1. Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2003; 23:2131–2137.
    1. Knijff-Dutmer EA, Koerts J, Nieuwland R, Kalsbeek-Batenburg EM, van de Laar MA. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum 2002; 46:1498–1503.
    1. Furman MI, Barnard MR, Krueger LA, Fox ML, Shilale EA, Lessard DM, et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38:1002–1006.
    1. George JN, Thoi LL, McManus LM, Reimann TA. Isolation of human platelet membrane microparticles from plasma and serum. Blood 1982; 60:834–840.
    1. George JN, Pickett EB, Heinz R. Platelet membrane microparticles in blood bank fresh frozen plasma and cryoprecipitate. Blood 1986; 68:307–309.
    1. Singh MV, Davidson DC, Jackson JW, Singh VB, Silva J, Ramirez SH, et al. Characterization of platelet-monocyte complexes in HIV-1-infected individuals: possible role in HIV-associated neuroinflammation. J Immunol 2014; 192:4674–4684.
    1. Nolz JC, Harty JT. IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking. J Clin Invest 2014; 124:1013–1026.
    1. Moore KL, Thompson LF. P-selectin (CD62) binds to subpopulations of human memory T lymphocytes and natural killer cells. Biochem Biophys Res Commun 1992; 186:173–181.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa