CR4 Signaling Contributes to a DC-Driven Enhanced Immune Response Against Complement-Opsonized HIV-1.

Marta Bermejo-Jambrina,Paul Hörtnagl,Michael Blatzer,Taras Valovka,Teodor E Yordanov,Wilfried Posch,Lukas A Huber,Doris Wilflingseder,Paula Jauregui-Onieva

doi:10.3389/fimmu.2020.02010

Marta Bermejo-Jambrina, Paul Hörtnagl + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2020.02010

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Abstract

Dendritic cells (DCs) possess intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. In turn, HIV-1 has evolved strategies to evade innate immune sensing by DCs resulting in suboptimal maturation and poor antiviral immune responses. We previously showed that complement-opsonized HIV-1 (HIV-C) was able to efficiently infect various DC subsets significantly higher than non-opsonized HIV-1 (HIV) and therefore also mediate a higher antiviral immunity. Thus, complement coating of HIV-1 might play a role with respect to viral control occurring early during infection via modulation of DCs. To determine in detail which complement receptors (CRs) expressed on DCs was responsible for infection and superior pro-inflammatory and antiviral effects, we generated stable deletion mutants for the α-chains of CR3, CD11b, and CR4, CD11c using CRISPR/Cas9 in THP1-derived DCs. We found that CD11c deletion resulted in impaired DC infection as well as antiviral and pro-inflammatory immunity upon exposure to complement-coated HIV-1. In contrast, sole expression of CD11b on DCs shifted the cells to an anti-inflammatory, regulatory DC type. We here illustrated that CR4 comprised of CD11c and CD18 is the major player with respect to DC infection associated with a potent early pro-inflammatory immune response. A more detailed characterization of CR3 and CR4 functions using our powerful tool might open novel avenues for early therapeutic intervention during HIV-1 infection.

Highlights

Dendritic cells (DCs) play a pivotal role in the defense against invading pathogens, acting as the most potent antigen-presenting cells (APCs) of the innate immune system [1,2,3]
We found that THP1-DCs differentiated in vitro into a functional DC-like phenotype (Figure 1A and Supplementary Figure S1 >monocyte-derived immature DCs (iDCs), monocyte-derived DCs (moDCs)), expressing high levels of both complement receptors (CRs), CR3, and CR4, as analyzed by the expression of CD11b, CD11c, and CD18
The profile of characteristic markers CD11b, CD11c, CD18, DC-SIGN, CD83, CD86, CD4, CXCR4, and HLA-DR on immature moDCs is illustrated in Supplementary Figure S1

Summary

Introduction

Dendritic cells (DCs) play a pivotal role in the defense against invading pathogens, acting as the most potent antigen-presenting cells (APCs) of the innate immune system [1,2,3]. They reside in the peripheral tissue, where they capture antigens and present them to naïve T cells in the lymph nodes. HIV-1 poorly replicates in DCs due to the activity of SAMHD1 [Sterile Alpha Motif (SAM) domain and histidine/aspartic acid (HD) domain containing protein 1] and effectively evades DC-mediated antiviral immunity [9]. The low-Beside hiding from DC-mediated immunity by low-level infection, the virus exploits DCs as shuttles to promote its own dissemination [11, 12]

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