Defining antigen-specific plasmablast and memory B cell subsets in blood following viral infection and vaccination of humans

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Abstract

Antigen-specific B cells bifurcate into antibody secreting cells (ASC) and memory B cells after infection or vaccination. ASCs or plasmablasts have been extensively studied in humans but less is known about B cells that get activated but do not differentiate into early plasmablasts. Here, we define the phenotype and transcriptional program of an antigen-specific B cell subset, referred to as activated B cells (ABC), that is distinct from ASCs and is committed to the memory B cell lineage. ABCs were detected in humans after infection with Ebola virus or influenza virus and also after vaccination. By simultaneously analyzing antigen-specific ASCs and ABCs in human blood after influenza vaccination we interrogated the clonal overlap and extent of somatic hypermutation (SHM) in the ASC (effector) and ABC (memory) lineages. Longitudinal tracking of vaccination-induced HA-specific clones revealed minimal increase in SHM over time suggesting that repeated annual immunization may have limitations in enhancing the quality of influenza-specific antibody.

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Most cited references 17

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FLASH: fast length adjustment of short reads to improve genome assemblies.

T. Magoc, S. L. Salzberg (2013)

Next-generation sequencing technologies generate very large numbers of short reads. Even with very deep genome coverage, short read lengths cause problems in de novo assemblies. The use of paired-end libraries with a fragment size shorter than twice the read length provides an opportunity to generate much longer reads by overlapping and merging read pairs before assembling a genome. We present FLASH, a fast computational tool to extend the length of short reads by overlapping paired-end reads from fragment libraries that are sufficiently short. We tested the correctness of the tool on one million simulated read pairs, and we then applied it as a pre-processor for genome assemblies of Illumina reads from the bacterium Staphylococcus aureus and human chromosome 14. FLASH correctly extended and merged reads >99% of the time on simulated reads with an error rate of <1%. With adequately set parameters, FLASH correctly merged reads over 90% of the time even when the reads contained up to 5% errors. When FLASH was used to extend reads prior to assembly, the resulting assemblies had substantially greater N50 lengths for both contigs and scaffolds. The FLASH system is implemented in C and is freely available as open-source code at http://www.cbcb.umd.edu/software/flash. t.magoc@gmail.com.

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Systems Biology of Seasonal Influenza Vaccination in Humans

Helder Nakaya, Jens Wrammert, Eva K. Lee … (2011)

We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV −/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.

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Commitment to the B-lymphoid lineage depends on the transcription factor Pax5.

S Nutt, B Heavey, A Rolink … (1999)

The Pax5 gene encoding the B-cell-specific activator protein (BSAP) is expressed within the haematopoietic system exclusively in the B-lymphoid lineage, where it is required in vivo for progression beyond the pro-B-cell stage. However, Pax5 is not essential for in vitro propagation of pro-B cells in the presence of interleukin-7 and stromal cells. Here we show that pro-B cells lacking Pax5 are also incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction. Pax5-/- pro-B cells are not restricted in their lineage fate, as stimulation with appropriate cytokines induces them to differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes and natural killer cells. As expected for a clonogenic haematopoietic progenitor with lymphomyeloid developmental potential, the Pax5-/- pro-B cell expresses genes of different lineage-affiliated programmes, and restoration of Pax5 activity represses this lineage-promiscuous transcription. Pax5 therefore plays an essential role in B-lineage commitment by suppressing alternative lineage choices.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 27 July 2016

Publication date (Electronic): 15 August 2016

Publication date (Print): October 2016

Publication date PMC-release: 15 February 2017

Volume: 17

Issue: 10

Pages: 1226-1234

Affiliations

[1 ]Emory Vaccine Center, School of Medicine, Emory University, Atlanta, GA 30322

[2 ]Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322

[3 ]Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322

[4 ]Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, GA 30322

[5 ]Department of Pathology, School of Medicine, Emory University, Atlanta, GA 30322

[6 ]Department of Urology, School of Medicine, Emory University, Atlanta, GA 30322

[7 ]Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, 30333

[8 ]Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105

[9 ]Department of Pathology, Stanford University, Stanford, CA 94305

[10 ]Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil

Author notes

Corresponding authors: Scott D. Boyd ( sboyd1@ 123456stanford.edu ), Rafi Ahmed ( rahmed@ 123456emory.edu )

[11]

These authors contributed equally.

Article

Manuscript ID: NIHMS800610

DOI: 10.1038/ni.3533

PMC ID: 5054979

PubMed ID: 27525369

SO-VID: 657915d8-0bcb-451a-82f2-e4cee7e395e5

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Defining antigen-specific plasmablast and memory B cell subsets in blood following viral infection and vaccination of humans

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Abstract

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Gamma Delta T cells

Most cited references 17

FLASH: fast length adjustment of short reads to improve genome assemblies.

Systems Biology of Seasonal Influenza Vaccination in Humans

Commitment to the B-lymphoid lineage depends on the transcription factor Pax5.

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