Vaccine-induced myeloid cell population dampens protective immunity to SIV
Yongjun Sui, … , Genoveffa Franchini, Jay A. Berzofsky
Yongjun Sui, … , Genoveffa Franchini, Jay A. Berzofsky
Published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2538-2549. https://doi.org/10.1172/JCI73518.
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Research Article

Vaccine-induced myeloid cell population dampens protective immunity to SIV

Abstract

Vaccines are largely evaluated for their ability to promote adaptive immunity, with little focus on the induction of negative immune regulators. Adjuvants facilitate and enhance vaccine-induced immune responses and have been explored for mediating protection against HIV. Using a regimen of peptide priming followed by a modified vaccinia Ankara (MVA) boost in a nonhuman primate model, we found that an SIV vaccine incorporating molecular adjuvants mediated partial protection against rectal SIVmac251 challenges. Animals treated with vaccine and multiple adjuvants exhibited a reduced viral load (VL) compared with those treated with vaccine only. Surprisingly, animals treated with adjuvant alone had reduced VLs that were comparable to or better than those of the vaccine-treated group. VL reduction was greatest in animals with the MHC class I allele Mamu-A*01 that were treated with adjuvant only and was largely dependent on CD8+ T cells. Early VLs correlated with Ki67+CCR5+CD4+ T cell frequency, while set-point VL was associated with expansion of a myeloid cell population that was phenotypically similar to myeloid-derived suppressor cells (MDSCs) and that suppressed T cell responses in vitro. MDSC expansion occurred in animals receiving vaccine and was not observed in the adjuvant-only group. Collectively, these results indicate that vaccine-induced MDSCs inhibit protective cellular immunity and suggest that preventing MDSC induction may be critical for effective AIDS vaccination.

Authors

Yongjun Sui, Alison Hogg, Yichuan Wang, Blake Frey, Huifeng Yu, Zheng Xia, David Venzon, Katherine McKinnon, Jeremy Smedley, Mercy Gathuka, Dennis Klinman, Brandon F. Keele, Sol Langermann, Linda Liu, Genoveffa Franchini, Jay A. Berzofsky

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Figure 5

MDSCs from PBMCs of the SIV vaccine–immunized (prior to infection) or vaccinated animals after SIVmac251 infection suppressed CD8+ T cell responses.

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MDSCs from PBMCs of the SIV vaccine–immunized (prior to infection) or va...
(A) Suppression effects of MDSCs (DR–CD11b+CD33+) on antigen-specific CD8+ T cell function in a coculture experiment. CD3+ T cells from PBMCs of SIV vaccine–immunized (Vaccinated) or vaccinated-then-SIVmac251-infected (Vacc-infected) macaques were stimulated with the SIV peptide pool (same as that used in the vaccination) in the presence of APCs. MDSCs from the same animal were added to the coculture at different ratios. CD8+ T cell proliferation was evaluated by CFSE dilution after 3 to 4 days of culture. Unstimulated T cells were used as a negative control. Right: Representative flow cytometry plot from 1 animal. Left: Results from 6 animals from 5 independent experiments. (B) Depletion of CD33+ cells enhanced CD8+ T cell responses. PBMCs or PBMCs with CD33 depletion (CD33 depleted) were stimulated with anti-CD3/28 antibodies for 3 to 4 days. CD8+ T cell proliferation was evaluated by CFSE dilution. Unstimulated PBMCs or CD33-depleted PBMCs were used as negative controls. Right: Representative flow cytometry plot from 1 animal. Left: Results from 6 animals from 5 independent experiments, R454# was an animal from another cohort with similar immunization. For the purified MDSC suppression assay (A), a least-squares regression of the slopes of the arcsine-transformed percentages over the ordinal MDSC/T cell ratios was used, rejecting the null hypothesis that the slopes were zero. The Wilcoxon signed-rank test was used for in vitro MDSC depletion assays (B).