Transcriptomic signatures of NK cells suggest impaired responsiveness in HIV-1 infection and increased activity post-vaccination

Costanzo, Margaret C.; Kim, Do-Hoon; Creegan, Matthew; Lal, Kerri G.; Ake, Julie A; Currier, Jeffrey R.; Streeck, Hendrik; Robb, Merlin L.; Michael, Nelson L.; Bolton, Diane L.; Steers, Nicholas J.; Eller, Michael A.

doi:10.1038/s41467-018-03618-w

Cited by 44 publications

(56 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we found high expression of mono 4-related proteins in NK cell 5 subsets, including a CD56 dim/neg subset (NK dim ). To validate these findings, we generated a transcriptomic NK-cell signature based on previous knowledge (Costanzo et al, 2018;Liberzon et al, 2011;Rieckmann et al, 2017;Subramanian et al, 2005) and calculated the signature enrichment scores across all monocyte subsets defined in map 1 (Figure 5C-D). This calculation revealed that the mono 4 subset was significantly enriched in NK-cell-specific transcripts.…”

Section: Backmapping Identifies Mono 4 As Bona Fide Cd56 Dim Nk Cellsmentioning

confidence: 93%

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

Günther

Cirovic

Baßler

et al. 2019

Preprint

View full text Add to dashboard Cite

Highlights  Defining a consensus of the human myeloid cell compartment in peripheral blood  3 monocytes subsets, pDC, cDC1, DC2, DC3 and precursor DC make up the compartment  Distinguish myeloid cell compartment from other cell spaces, e.g. the NK cell space 5  Providing a generalizable method for building consensus maps for the life sciences 4 Abstract Single-cell genomic techniques are opening new avenues to understand the basic units of life.Large international efforts, such as those to derive a Human Cell Atlas, are driving progress in this area; here, cellular map generation is key. To expedite the inevitable iterations of these underlying maps, we have developed a rule-based data-informed approach to build next 5 generation cellular consensus maps. Using the human dendritic-cell and monocyte compartment in peripheral blood as an example, we performed computational integration of previous, partially overlapping maps using an approach we termed 'backmapping', combined with multi-color flowcytometry and index sorting-based single-cell RNA-sequencing. Our general strategy can be applied to any atlas generation for humans and other species. 10

show abstract

Section: Backmapping Identifies Mono 4 As Bona Fide Cd56 Dim Nk Cellsmentioning

confidence: 93%

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

Günther

Cirovic

Baßler

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Also, NK cells were shown to orientate the B cell response and the underlying affinity maturation via the restriction of follicular helper T cells, a feature that is key in the generation of broadly neutralizing antibodies . NK cell functions are influenced by vaccination and infection . In addition, recent findings in mice, macaques, and humans indicate that NK cells show adaptive‐like features .…”

Section: Introductionmentioning

confidence: 99%

“…13 NK cell functions are influenced by vaccination and infection. 14,15 In addition, recent findings in mice, macaques, and humans indicate that NK cells show adaptive-like features. [16][17][18][19] However, it is not yet fully clear how these findings can be exploited to…”

mentioning

confidence: 99%

NK cell immune responses differ after prime and boost vaccination

Palgen

Tchitchek

Huot

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

A better understanding of innate responses induced by vaccination is critical for designing optimal vaccines. Here, we studied the diversity and dynamics of the NK cell compartment after prime‐boost immunization with the modified vaccinia virus Ankara using cynomolgus macaques as a model. Mass cytometry was used to deeply characterize blood NK cells. The NK cell subphenotype composition was modified by the prime. Certain phenotypic changes induced by the prime were maintained over time and, as a result, the NK cell composition prior to boost differed from that before prime. The key phenotypic signature that distinguished NK cells responding to the boost from those responding to the prime included stronger expression of several cytotoxic, homing, and adhesion molecules, suggesting that NK cells at recall were functionally distinct. Our data reveal potential priming or imprinting of NK cells after the first vaccine injection. This study provides novel insights into prime‐boost vaccination protocols that could be used to optimize future vaccines.

show abstract

“…Conversely, the inhibitory receptor genes LILRB1, LAG3, and TIGIT were upregulated and KLRB1, LAIR2, and SIGLEC7 were down-regulated. In addition, we observed increased expression of BIRC3, TNF, and IFNG, which have been proposed to be NK cell activation markers 22 . Despite the beneficial roles of NK cells in antiviral responses, their function is known to be impaired by chronic HIV infection 60 .…”

Section: Identification Of Novel Genes Associated With T Cell Exhaustionmentioning

confidence: 65%

“…Despite the great promise of reversal of T cell exhaustion as a curative strategy for HIV, little is known about the mechanisms involved in immune cell exhaustion in HIV-infected individuals at the transcriptomic level. In addition, chronic HIV infection is associated with exhaustion not only of T cells but also of B and NK cells [20][21][22] . Therefore, it is possible that these three exhausted cell populations could cooperate in contributing to host immune system dysfunction, allowing unchecked HIV replication and disease progression.…”

mentioning

confidence: 99%

An Atlas of Immune Cell Exhaustion in HIV-Infected Individuals Revealed by Single-Cell Transcriptomics

Wang

Zhang

Hui

et al. 2019

Preprint

View full text Add to dashboard Cite

Chronic infection with human immunodeficiency virus (HIV) can cause progressive loss of immune cell function, or exhaustion, which impairs control of virus replication. However, little is known about the development and maintenance, as well as heterogeneity of immune cell exhaustion. Here, we investigated the effects of HIV infection on immune cell exhaustion at the transcriptomic level by analyzing single-cell RNA sequencing of peripheral blood mononuclear cells from two healthy subjects (15,121 cells) and six HIV-infected donors (28,610 cells). We identified nine immune cell clusters and eight T cell subclusters according to their unique gene expression programs; three of these (exhausted CD4 + and CD8 + T cells and interferonresponsive CD8 + T cells) were detected only in samples from HIV-infected donors. An inhibitory receptor KLRG1 was identified in the exhausted T cell populations and further characterized in HIV infected individuals. We identified a novel HIV-1 specific exhausted CD8 + T cell population expressing KLRG1, TIGIT, and T-bet dim Eomes hi markers. Ex-vivo antibody blockade of KLRG1 restored the function of HIV-specific exhausted CD8 + T cells demonstrating the contribution of KLRG1 + population to T cell exhaustion and providing a novel target for developing immunotherapy to treat HIV chronic infection. Analysis of gene signatures also revealed impairment of B cell and NK cell function in HIVinfected donors. These data provide a comprehensive analysis of gene signatures associated with immune cell exhaustion during HIV infection, which could be useful in understanding exhaustion mechanisms and developing new cure therapies. We thank Drs. Doug Richman, Mario Stevenson, and Jon Karn for helpful discussions, Kristen Jepsen at the IGM Genomics Center for help with scRNA-seq, Celsa Spina of UCSD CFAR for flow analysis and members of the Rana lab for helpful discussions and advice. We also thank Dr. Song Chen for advice and help in sample preparation and data analysis.

show abstract

Transcriptomic signatures of NK cells suggest impaired responsiveness in HIV-1 infection and increased activity post-vaccination

Cited by 44 publications

References 69 publications

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

NK cell immune responses differ after prime and boost vaccination

An Atlas of Immune Cell Exhaustion in HIV-Infected Individuals Revealed by Single-Cell Transcriptomics

Contact Info

Product

Resources

About