Immunologic Research

, Volume 65, Issue 4, pp 869–879 | Cite as

The levels of DNGR-1 and its ligand-bearing cells were altered after human and simian immunodeficiency virus infection

  • Wen-Rong Yao
  • Dong Li
  • Lei Yu
  • Feng-Jie Wang
  • Hui Xing
  • Gui-Bo Yang
Original Article

Abstract

Dendritic cell NK lectin Group Receptor-1 (DNGR-1), also known as C-type lectin domain family 9, member A (CLEC9A), is a member of C-type lectin receptor superfamily expressed primarily on dendritic cells (DC) that excel in cross-presentation of exogenous antigens. To find out whether and how it is affected in human immunodeficiency virus infections or acquired immunodeficiency syndromes (HIV/AIDS), DNGR-1 expression and DNGR-1-binding cells in simian/human immunodeficiency virus (SHIV) and simian immunodeficiency virus (SIV)-infected rhesus macaques and antiretroviral therapy (ART)-treated AIDS patients were examined by real-time RT-PCR, flow cytometry, and confocal microscopy. DNGR-1 expression was observed in both lymphoid and non-lymphoid tissues including gut-associated lymphoid tissues (GALT) of rhesus macaques. DNGR-1 mRNA levels were significantly reduced in the blood while significantly elevated in the GALT of SHIV/SIV-infected rhesus macaques. DNGR-1 transcription levels were also significantly reduced in the blood of ART-treated AIDS patients irrespective of viral status. White blood cells with exposed DNGR-1 ligands were significantly increased in ART-treated AIDS patients, while significantly decreased in SIV-infected rhesus macaques. These data indicate that DNGR-1 expression, and by extension, the function of cross-presentation of antigens associated with dead/damaged cells might be compromised in HIV/SIV infection, which might play a role in HIV/AIDS pathogenesis and should be taken into consideration in therapeutic AIDS vaccine development.

Keywords

DNGR-1 CLEC9A HIV-1 SHIV/SIV infection ART Rhesus macaques 

Notes

Acknowledgements

The study was funded by MOST of China (Grant number 2013ZX10001004-002-001) and NNSF of China (Grant number 81571607). The authors would like to take the opportunity to express the appreciation to those who contributed the blood samples for this study.

Compliance with ethical standards

Conflict of interest

No competing financial interests exist.

Supplementary material

12026_2017_8925_Fig7_ESM.gif (84 kb)
Figure S1

DNGR-1 immunoreactive cells in intestinal mucosa. DNGR-1 immunoreactive cells were detected with anti-rhDNGR-1 polyclonal antibody raised in our laboratory. TSA-tyramide signal amplification method was used. Images of DNGR-1 immunoreactivity (green), auto-fluoresence (mostly by macrophages, red), nuclei (blue) and DIC including cells with endogenous peroxidase activity (deep black) were obtained with laser scanning confocal microscope. Original amplification, 40× (GIF 83 kb)

12026_2017_8925_MOESM1_ESM.tif (935 kb)
High resolution image (TIFF 935 kb)
12026_2017_8925_Fig8_ESM.gif (18 kb)
Figure S2

Correlations between DNGR-1 mRNA levels and CD4 count in group V+R- and between DNGR-1 mRNA levels and plasma viral load in group V+R+. Data were log transformed and Pearson’s tests were performed. (GIF 17 kb)

12026_2017_8925_MOESM2_ESM.tif (414 kb)
High resolution image (TIFF 414 kb)
12026_2017_8925_MOESM3_ESM.doc (38 kb)
Table S1 (DOC 38 kb)

References

  1. 1.
    Sancho D, Reis e Sousa C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol. 2012;30:491–529.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Caminschi I, Proietto AI, Ahmet F, et al. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood. 2008;112:3264–73.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Huysamen C, Willment JA, Dennehy KM, Brown GD. CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J Biol Chem. 2008;283:16693–701.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sancho D, Mourao-Sa D, Joffre OP, et al. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J Clin Invest. 2008;118:2098–110.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sancho D, Joffre OP, Keller AM, et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature. 2009;458:899–903.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ahrens S, Zelenay S, Sancho D, et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity. 2012;36:635–45.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang JG, Czabotar PE, Policheni AN, et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity. 2012;36:646–57.CrossRefPubMedGoogle Scholar
  8. 8.
    Hanc P, Fujii T, Iborra S, et al. Structure of the complex of F-actin and DNGR-1, a C-type lectin receptor involved in dendritic cell cross-presentation of dead cell-associated antigens. Immunity. 2015;42:839–49.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol. 2012;12:557–69.CrossRefPubMedGoogle Scholar
  10. 10.
    Li J, Ahmet F, Sullivan LC, et al. Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates. Eur J Immunol. 2015;45:854–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Idoyaga J, Lubkin A, Fiorese C, et al. Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to langerin, DEC205, and Clec9A. Proc Natl Acad Sci U S A. 2011;108:2384–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chehimi J, Campbell DE, Azzoni L, et al. Persistent decreases in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected individuals. J Immunol. 2002;168:4796–801.CrossRefPubMedGoogle Scholar
  13. 13.
    Wu L, KewalRamani VN. Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol. 2006;6:859–68.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dutertre CA, Amraoui S, DeRosa A, et al. Pivotal role of M-DC8(+) monocytes from viremic HIV-infected patients in TNFalpha overproduction in response to microbial products. Blood. 2012;120:2259–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Dutertre CA, Jourdain JP, Rancez M, et al. TLR3-responsive, XCR1+, CD141(BDCA-3)+/CD8alpha+-equivalent dendritic cells uncovered in healthy and simian immunodeficiency virus-infected rhesus macaques. J Immunol. 2014;192:4697–708.CrossRefPubMedGoogle Scholar
  16. 16.
    van den Berg LM, Cardinaud S, van der Aar AM, et al. Langerhans cell-dendritic cell cross-talk via langerin and hyaluronic acid mediates antigen transfer and cross-presentation of HIV-1. J Immunol. 2015;195:1763–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Reyes-Rodriguez AL, Reuter MA, McDonald D. Dendritic cells enhance HIV infection of memory CD4(+) T cells in human lymphoid tissues. AIDS Res Hum Retrovir. 2016;32:203–10.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Poulin LF, Salio M, Griessinger E, et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207:1261–71.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Schreibelt G, Klinkenberg LJ, Cruz LJ, et al. The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood. 2012;119:2284–92.CrossRefPubMedGoogle Scholar
  20. 20.
    Breton G, Lee J, Zhou YJ, et al. Circulating precursors of human CD1c+ and CD141+ dendritic cells. J Exp Med. 2015;212:401–13.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kinloch-de Loes S, Hoen B, Smith DE, et al. Impact of therapeutic immunization on HIV-1 viremia after discontinuation of antiretroviral therapy initiated during acute infection. J Infect Dis. 2005;192:607–17.CrossRefPubMedGoogle Scholar
  22. 22.
    Macatangay BJ, Riddler SA, Wheeler ND, et al. Therapeutic vaccination with dendritic cells loaded with autologous HIV type 1-infected apoptotic cells. J Infect Dis. 2016;213:1400–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Coates PT, Barratt-Boyes SM, Zhang L, et al. Dendritic cell subsets in blood and lymphoid tissue of rhesus monkeys and their mobilization with Flt3 ligand. Blood. 2003;102:2513–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Brown KN, Trichel A, Barratt-Boyes SM. Parallel loss of myeloid and plasmacytoid dendritic cells from blood and lymphoid tissue in simian AIDS. J Immunol. 2007;178:6958–67.CrossRefPubMedGoogle Scholar
  25. 25.
    Yang GB, Lei N, Zong CM, Duan JZ, Xing H, Shao Y. Elevated frequency of CD1c+ myeloid dendritic cells in the peripheral blood mononuclear cells of simian/human immunodeficiency virus (SHIV) and simian immunodeficiency virus (SIV) repeatedly infected Chinese rhesus macaques. Cell Immunol. 2011;271:36–43.CrossRefPubMedGoogle Scholar
  26. 26.
    Reeves RK, Evans TI, Gillis J, et al. SIV infection induces accumulation of plasmacytoid dendritic cells in the gut mucosa. J Infect Dis. 2012;206:1462–8.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wonderlich ER, Wu WC, Normolle DP, Barratt-Boyes SM. Macrophages and myeloid dendritic cells lose T cell-stimulating function in simian immunodeficiency virus infection associated with diminished IL-12 and IFN-alpha production. J Immunol. 2015;195:3284–92.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Evans TI, Li H, Schafer JL, et al. SIV-induced translocation of bacterial products in the liver mobilizes myeloid dendritic and natural killer cells associated with liver damage. J Infect Dis. 2016;213:361–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Yang GB, Wang Y, Babaahmady K, et al. Immunization with recombinant macaque major histocompatibility complex class I and II and human immunodeficiency virus gp140 inhibits simian-human immunodeficiency virus infection in macaques. J Gen Virol. 2012;93:1506–18.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang Y, Yang GB. Alteration of polymeric immunoglobulin receptor and neonatal Fc receptor expression in the gut mucosa of immunodeficiency virus-infected rhesus macaques. Scand J Immunol. 2016;83:235–43.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang WJ, Wang Y, Yu K, et al. Associated changes in the transcription levels of IL-17A and tight junction-associated genes in the duodenal mucosa of rhesus macaques repeatedly exposed to simian/human immunodeficiency virus. Exp Mol Pathol. 2014;97:225–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang Y, Yao WR, Duan JZ, Xu W, Yang GB. Mucosal addressin cell adhesion molecule-1 of rhesus macaques: molecular cloning, expression, and alteration after viral infection. Dig Dis Sci. 2014;59:2433–43.CrossRefPubMedGoogle Scholar
  33. 33.
    Yao W, Yang G. The expression of C-type lectin-like domain of DNGR-1 molecules of Chinese rhesus macaques in E. coli. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2014;30:489–92.PubMedGoogle Scholar
  34. 34.
    Jongbloed SL, Kassianos AJ, McDonald KJ, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–60.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Poulin LF, Reyal Y, Uronen-Hansson H, et al. DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues. Blood. 2012;119:6052–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Segura E, Valladeau-Guilemond J, Donnadieu MH, Sastre-Garau X, Soumelis V, Amigorena S. Characterization of resident and migratory dendritic cells in human lymph nodes. J Exp Med. 2012;209:653–60.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kelly A, Fahey R, Fletcher JM, et al. CD141(+) myeloid dendritic cells are enriched in healthy human liver. J Hepatol. 2014;60:135–42.CrossRefPubMedGoogle Scholar
  38. 38.
    Quintana E, Fernandez A, Velasco P, et al. DNGR-1(+) dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia. 2015;63:2231–48.CrossRefPubMedGoogle Scholar
  39. 39.
    Donaghy H, Pozniak A, Gazzard B, et al. Loss of blood CD11c(+) myeloid and CD11c(−) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood. 2001;98:2574–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Pacanowski J, Kahi S, Baillet M, et al. Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection. Blood. 2001;98:3016–21.CrossRefPubMedGoogle Scholar
  41. 41.
    Soumelis V, Scott I, Gheyas F, et al. Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. Blood. 2001;98:906–12.CrossRefPubMedGoogle Scholar
  42. 42.
    Sabado RL, O'Brien M, Subedi A, et al. Evidence of dysregulation of dendritic cells in primary HIV infection. Blood. 2010;116:3839–52.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kwa S, Kannanganat S, Nigam P, et al. Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques. Blood. 2011;118:2763–73.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zelenay S, Keller AM, Whitney PG, et al. The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J Clin Invest. 2012;122:1615–27.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Finkel TH, Tudor-Williams G, Banda NK, et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med. 1995;1:129–34.CrossRefPubMedGoogle Scholar
  46. 46.
    Gougeon ML. Apoptosis as an HIV strategy to escape immune attack. Nat Rev Immunol. 2003;3:392–404.CrossRefPubMedGoogle Scholar
  47. 47.
    Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353–63.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Doitsh G, Galloway NL, Geng X, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 2014;505:509–14.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390:350–1.CrossRefPubMedGoogle Scholar
  50. 50.
    Uderhardt S, Herrmann M, Oskolkova OV, et al. 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. Immunity. 2012;36:834–46.CrossRefPubMedGoogle Scholar
  51. 51.
    Rock KL, Kono H. The inflammatory response to cell death. Annu Rev Pathol. 2008;3:99–126.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Bastard JP, Fellahi S, Couffignal C, et al. Increased systemic immune activation and inflammatory profile of long-term HIV-infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity. J Antimicrob Chemother. 2015;70:1816–24.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Wen-Rong Yao
    • 1
  • Dong Li
    • 1
  • Lei Yu
    • 1
  • Feng-Jie Wang
    • 1
  • Hui Xing
    • 1
  • Gui-Bo Yang
    • 1
  1. 1.National Center for AIDS/STD Control and PreventionChina CDCBeijingPeople’s Republic of China

Personalised recommendations