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Cellular and Molecular Life Sciences

, Volume 75, Issue 10, pp 1871–1887 | Cite as

Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs

  • Lamine Alaoui
  • Gustavo Palomino
  • Sandy Zurawski
  • Gerard Zurawski
  • Sixtine Coindre
  • Nathalie Dereuddre-Bosquet
  • Camille Lecuroux
  • Cecile Goujard
  • Bruno Vaslin
  • Christine Bourgeois
  • Pierre Roques
  • Roger Le Grand
  • Olivier Lambotte
  • Benoit FavierEmail author
Original Article

Abstract

Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.

Keywords

ILT4 HLA class I Immune checkpoint ITIM Innate immunity LILR SIRPa 

Notes

Acknowledgements

We thank the IDMIT infrastructure staff and Florian Meurisse for technical assistance. We also thank the ANRS cohorts CO6 PRIMO and CO21 CODEX for helpful collaboration and Anne Sophie Beignon for critical reading of the manuscript and helpful discussions. These works were supported by grants from the “Agence Nationale de Recherches sur le SIDA et les hépatites virales” under statement numbers 14-067, 16–035, University of Paris-Sud (Attractivité), European Union FP7 project (grant agreement no. 261202 (ICRES)), French government “Programme d’Investissements d’Avenir” (PIA) under Grant ANR-11-INBS-0008 funding the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France) infrastructure and PIA grant ANR-10-EQPX-02-01 funding the FlowCyTech facility. G. Palomino was supported by a post-doctoral fellowship from Brazil government (Programa Ciência sem Fronteiras).

Supplementary material

18_2017_2712_MOESM1_ESM.eps (3.1 mb)
Figure S1. Generation and reactivity of anti-LILRB2 antibody (clone 17E5.3E9). (A) Amino acid sequence of human LILRB2 extracellular domain used to generate antibody 17E5.3E9. (B) Analysis of anti-LILRB2 antibody (clone 17E5.3E9) staining on cDCs, monocytes, neutrophils, eosinophils, CD4+ and CD8+ T cells, B cells and NK cells of healthy human and cynomolgus macaque blood samples. (C) Upregulation of LILRB2 is detected by 17E5.3E9 antibody on healthy human and cynomolgus macaque neutrophils stimulated with TNF-a. Flow cytometry analysis of LILRB2 at the surface of unstimulated (full line) or stimulated (dotted line) neutrophils for 30 min with TNF-a (100 ng/mL). Gray filled curve shows cells stained with isotype-matched control mAb. Data are representative of three independent experiments. (EPS 3132 kb)
18_2017_2712_MOESM2_ESM.eps (1.6 mb)
Figure S2. Flow cytometry gating strategy used to identify cell subsets of PBMCs from HIV-1+ patients. cDCs (CD1c+) were identified as Lin/HLA-DR+/CD16/CD14/CD123/CD11c+/CD1c+. Results shown are representative between individuals. (EPS 1685 kb)
18_2017_2712_MOESM3_ESM.eps (1.1 mb)
Figure S3. Characterization of HLA-DR expression level on cDCs during the early phase of HIV-1 infection. Analysis of HLA-DR surface expression on cDCs from blood samples of early HIV-1-infected patients before (primary HIV+) or after 1 year of cART (HIV+ cART+), HIV-1-infected elite controller patients (HIC), and HIV-1-non-infected controls (HIV-). Data are represented as mean fluorescence intensity with statistical analysis performed using the Mann–Whitney U test between HIC (n = 6), and primary HIV+ patients (n = 7) (p < 0,05 is considered significant). (EPS 1133 kb)
18_2017_2712_MOESM4_ESM.eps (2 mb)
Figure S4. Characterization of LILRB2 expression on immune cell subsets from secondary lymphoid organs of cynomolgus macaques. (A) Flow cytometry gating strategy used to identify cDCs and T and B cells of peripheral lymph nodes and spleen of cynomolgus macaques. cDCs were identified as CD45+/Lin(CD3/CD8/CD20)/HLA-DR+/CD163/CD123/CD1c+. (B) Flow cytometry analysis of LILRB2 expression on cDCs and on T and B cells from both peripheral and mesenteric lymph nodes, spleen, and peripheral blood (n = 4). (EPS 2019 kb)
18_2017_2712_MOESM5_ESM.eps (1.4 mb)
Figure S5. Follow-up of LILRB2 and MHC-I expression on monocytes and macrophages during infection of cynomolgus macaques by SIVmac251. (A) Monocyte cell counts during SIVmac251 infection, at 1000 AID50/mL, of 3 three female cynomolgus macaques. LILRB2 and MHC-I surface expression profiles of (B) blood monocytes and (C) lymph node macrophages. (D) Modulation of LILRB2 and MHC-I surface expression on blood monocytes from seven cynomolgus macaques followed at various time points during early (days 4 to 7, days 9 to 11, days 14 to 21, days 22 to 42) and advanced (days 57 to 100) phases of SIVmac251 infection. Data are shown as the fold change of surface expression relative to baseline (represented with dashed line). Statistical analyses were carried-out using the Wilcoxon matched-pairs signed rank test (p < 0.05 is considered significant). (EPS 1393 kb)
18_2017_2712_MOESM6_ESM.eps (1.3 mb)
Figure S6. Analysis of LILRB2 and MHC-I expression during SIV infection of three male cynomolgus macaques. (A) Plasma viral load of SIVmac251 infection at 1000 AID50/mL. (B) Modulation of LILRB2 (left panel) and MHC-I (right panel) expression on blood cDCs and (C) monocytes (CD14+/CD16). (D) Follow-up of LILRB2 surface expression on cDCs and macrophages isolated from peripheral lymph nodes of cynomolgus macaques during early (D + 14) and late (D + 85) phases of SIVmac251 infection. The surface expression of LILRB2 and MHC-I was determined by the mean fluorescence Intensity of each marker by flow cytometry. (EPS 1284 kb)
18_2017_2712_MOESM7_ESM.eps (1.1 mb)
Figure S7. Follow-up of SIRPa inhibitory receptor expression on cDCs during SIV infection of cynomolgus macaques. (A) Modulation of SIRPa expression on blood cDCs of three female cynomolgus macaques infected with 1000 AID50/mL of SIVmac251. (B) SIRPa expression on cDCs from secondary lymphoid tissue was evaluated from sampled peripheral lymph nodes at various time points after SIV infection. Data are represented as the mean Fluorescence Intensity. (EPS 1119 kb)
18_2017_2712_MOESM8_ESM.eps (1.1 mb)
Figure S8. Evolution of blood leucocyte counts during CHIKV infection of cynomolgus macaques. The evolution of cell counts of four cynomolgus macaques infected with the CHIKV-LR2006-OPY1 strain at a dose of 100 AID50/mL. (A) Follow-up of cDC counts analyzed by flow cytometry using Trucount tubes (BD biosciences). (B) Analysis of absolute blood cell numbers to follow the evolution of lymphocyte, monocyte, and granulocyte numbers using automated cell counts (HmX AL System, Beckman Coulter). (EPS 1111 kb)
18_2017_2712_MOESM9_ESM.eps (4.2 mb)
Figure S9. Schematic of LILRB2/MHC-I inhibitory axis regulation in cDCs of lymph nodes during HIV/SIV infection. (1) IL-10 and IFN-I stimulation along with HIV-1 sensing by TLR7/8 induce (2) the upregulation of LILRB2 expression allowing higher (3) Cis or Trans interactions with MHC-I ligands leading to (4) cDC dysfunctions. (EPS 4300 kb)
18_2017_2712_MOESM10_ESM.eps (1.2 mb)
Table S1. Monoclonal antibodies used for flow cytometry analysis of human and cynomolgus macaque samples. (EPS 1180 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Lamine Alaoui
    • 1
  • Gustavo Palomino
    • 1
  • Sandy Zurawski
    • 3
  • Gerard Zurawski
    • 3
  • Sixtine Coindre
    • 1
  • Nathalie Dereuddre-Bosquet
    • 1
  • Camille Lecuroux
    • 1
  • Cecile Goujard
    • 2
  • Bruno Vaslin
    • 1
  • Christine Bourgeois
    • 1
  • Pierre Roques
    • 1
  • Roger Le Grand
    • 1
  • Olivier Lambotte
    • 1
    • 2
  • Benoit Favier
    • 1
    Email author
  1. 1.CEA-Université Paris Sud 11-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, IBJF, DRFFontenay-aux-RosesFrance
  2. 2.Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Groupe Hospitalier Universitaire Paris Sud, Hôpital BicêtreLe Kremlin-BicêtreFrance
  3. 3.Baylor Institute for Immunology ResearchDallasUSA

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