Publications by authors named "Rafi Ahmed"

331 Publications

Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant.

Cell Host Microbe 2021 Mar 20. Epub 2021 Mar 20.

Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA; Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA; Yerkes National Primate Research Center, Atlanta, GA 30329, USA. Electronic address:

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies. We compared antibody binding and live virus neutralization of sera from naturally infected and Moderna-vaccinated individuals against two SARS-CoV-2 variants: B.1 containing the spike mutation D614G and the emerging B.1.351 variant containing additional spike mutations and deletions. Sera from acutely infected and convalescent COVID-19 patients exhibited a 3-fold reduction in binding antibody titers to the B.1.351 variant receptor-binding domain of the spike protein and a 3.5-fold reduction in neutralizing antibody titers against SARS-CoV-2 B.1.351 variant compared to the B.1 variant. Similar results were seen with sera from Moderna-vaccinated individuals. Despite reduced antibody titers against the B.1.351 variant, sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351, suggesting that protective humoral immunity may be retained against this variant.
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http://dx.doi.org/10.1016/j.chom.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980225PMC
March 2021

Characterization of neutralizing versus binding antibodies and memory B cells in COVID-19 recovered individuals from India.

Virology 2021 06 5;558:13-21. Epub 2021 Mar 5.

ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India. Electronic address:

India is one of the most affected countries by COVID-19 pandemic; but little is understood regarding immune responses to SARS-CoV-2 in this region. Herein we examined SARS-CoV-2 neutralizing antibodies, IgG, IgM, IgA and memory B cells in COVID-19 recovered individual from India. While a vast majority of COVID-19 recovered individuals showed SARS-CoV-2 RBD-specific IgG, IgA and IgM antibodies (38/42, 90.47%; 21/42, 50%; 33/42, 78.57% respectively), only half of them had appreciable neutralizing antibody titers. RBD-specific IgG, but not IgA or IgM titers, correlated with neutralizing antibody titers and RBD-specific memory B cell frequencies. These findings have timely significance for identifying potential donors for plasma therapy using RBD-specific IgG assays as surrogate measurement for neutralizing antibodies in India. Further, this study provides useful information needed for designing large-scale studies towards understanding of inter-individual variation in immune memory to SARS CoV-2 natural infection for future vaccine evaluation and implementation efforts.
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http://dx.doi.org/10.1016/j.virol.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934698PMC
June 2021

Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant.

bioRxiv 2021 Feb 22. Epub 2021 Feb 22.

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies to neutralize these variants. We compared antibody binding and live virus neutralization of sera from naturally infected and spike mRNA vaccinated individuals against a circulating SARS-CoV-2 B.1 variant and the emerging B.1.351 variant. In acutely-infected (5-19 days post-symptom onset), convalescent COVID-19 individuals (through 8 months post-symptom onset) and mRNA-1273 vaccinated individuals (day 14 post-second dose), we observed an average 4.3-fold reduction in antibody titers to the B.1.351-derived receptor binding domain of the spike protein and an average 3.5-fold reduction in neutralizing antibody titers to the SARS-CoV-2 B.1.351 variant as compared to the B.1 variant (spike D614G). However, most acute and convalescent sera from infected and all vaccinated individuals neutralize the SARS-CoV-2 B.1.351 variant, suggesting that protective immunity is retained against COVID-19.
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http://dx.doi.org/10.1101/2021.02.20.432046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924283PMC
February 2021

Infection and mRNA-1273 vaccine antibodies neutralize SARS-CoV-2 UK variant.

medRxiv 2021 Feb 5. Epub 2021 Feb 5.

Antibody responses against the SARS-CoV-2 Spike protein correlate with protection against COVID-19. Serum neutralizing antibodies appear early after symptom onset following SARS-CoV-2 infection and can last for several months. Similarly, the messenger RNA vaccine, mRNA-1273, generates serum neutralizing antibodies that are detected through at least day 119. However, the recent emergence of the B.1.1.7 variant has raised significant concerns about the breadth of these neutralizing antibody responses. In this study, we used a live virus neutralization assay to compare the neutralization potency of sera from infected and vaccinated individuals against a panel of SARS-CoV-2 variants, including SARS-CoV-2 B.1.1.7. We found that both infection- and vaccine-induced antibodies were effective at neutralizing the SARS-CoV-2 B.1.1.7 variant. These findings support the notion that in the context of the UK variant, vaccine-induced immunity can provide protection against COVID-19. As additional SARS-CoV-2 viral variants continue to emerge, it is crucial to monitor their impact on neutralizing antibody responses following infection and vaccination.
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http://dx.doi.org/10.1101/2021.02.02.21250799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872377PMC
February 2021

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.

J Exp Med 2021 04;218(4)

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.
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http://dx.doi.org/10.1084/jem.20202486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871457PMC
April 2021

Immunomodulatory Low-Dose Whole-Lung Radiation for Patients with Coronavirus Disease 2019-Related Pneumonia.

Int J Radiat Oncol Biol Phys 2021 03 16;109(4):867-879. Epub 2020 Dec 16.

Emory University School of Medicine, Atlanta, Georgia; Department of Infectious Disease, Emory University, Atlanta, Georgia. Electronic address:

Purpose: Phase 1 clinical trials have established low-dose, whole-lung radiation therapy (LD-RT) as safe for patients with coronavirus disease 2019 (COVID-19)-related pneumonia. By focally dampening cytokine hyperactivation, LD-RT may improve disease outcomes through immunomodulation.

Methods And Materials: Patients with COVID-19-related pneumonia were treated with 1.5 Gy whole-lung LD-RT, followed for 28 days or until hospital discharge, and compared with age- and comorbidity-matched controls meeting identical disease severity criteria. Eligible patients were hospitalized, severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) positive, had radiographic consolidations, and required supplemental oxygen but had not rapidly declined on admission or before drug therapy or LD-RT. Efficacy endpoints were time to clinical recovery, radiographic improvement, and biomarker response.

Results: Ten patients received whole-lung LD-RT between April 24 and May 24, 2020 and were compared with 10 control patients blindly matched by age and comorbidity. Six controls received COVID-19 drug therapies. Median time to clinical recovery was 12 days in the control cohort compared with 3 days in the LD-RT cohort (hazard ratio 2.9, P = .05). Median time to hospital discharge (20 vs 12 days, P = .19) and intubation rates (40% vs 10%, P = .12) in the control and LD-RT cohorts were compared. Median time from admission to recovery was 10 versus 13 days (P = .13). Hospital duration average was 19 versus 22.6 days (P = .53). Average hospital days on supplemental oxygen of any duration was 13.1 versus 14.7 days (P = .69). Average days with a documented fever was 1 versus 4.3 days (P = .12). Twenty-eight-day overall survival was 90% for both cohorts. The LD-RT cohort trended toward superior rates of improved radiographs (P = .12) and delirium (P < .01). Statistically significant reductions were observed in numerous hematologic, cardiac, hepatic, and inflammatory markers.

Conclusions: A prospective cohort of predominantly elderly hospitalized patients with COVID-19-related pneumonia were recovered to room air quicker than age- and comorbidity-matched controls, with trending or significant improvements in delirium, radiographs, and biomarkers, and no significant acute toxicity. Low-dose, whole-lung radiation for patients with COVID-19-related pneumonia appears safe and may be an effective immunomodulatory treatment. Larger prospective randomized trials are needed to define the efficacy of LD-RT for COVID-19.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832642PMC
March 2021

Defining HPV-specific B cell responses in patients with head and neck cancer.

Nature 2020 Nov 18. Epub 2020 Nov 18.

Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.

Tumours often contain B cells and plasma cells but the antigen specificity of these intratumoral B cells is not well understood. Here we show that human papillomavirus (HPV)-specific B cell responses are detectable in samples from patients with HPV-positive head and neck cancers, with active production of HPV-specific IgG antibodies in situ. HPV-specific antibody secreting cells (ASCs) were present in the tumour microenvironment, with minimal bystander recruitment of influenza-specific cells, suggesting a localized and antigen-specific ASC response. HPV-specific ASC responses correlated with titres of plasma IgG and were directed against the HPV proteins E2, E6 and E7, with the most dominant response against E2. Using intratumoral B cells and plasma cells, we generated several HPV-specific human monoclonal antibodies, which exhibited a high degree of somatic hypermutation, consistent with chronic antigen exposure. Single-cell RNA sequencing analyses detected activated B cells, germinal centre B cells and ASCs within the tumour microenvironment. Compared with the tumour parenchyma, B cells and ASCs were preferentially localized in the tumour stroma, with well-formed clusters of activated B cells indicating ongoing germinal centre reactions. Overall, we show that antigen-specific activated and germinal centre B cells as well as plasma cells can be found in the tumour microenvironment. Our findings provide a better understanding of humoral immune responses in human cancer and suggest that tumour-infiltrating B cells could be harnessed for the development of therapeutic agents.
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http://dx.doi.org/10.1038/s41586-020-2931-3DOI Listing
November 2020

Heat Shock Protein-90 Inhibition Alters Activation of Pancreatic Stellate Cells and Enhances the Efficacy of PD-1 Blockade in Pancreatic Cancer.

Mol Cancer Ther 2021 01 9;20(1):150-160. Epub 2020 Oct 9.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti-PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti-PD-1 had a significantly increased CD8 and CD4 T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF and enhances the efficacy of anti-PD-1 blockade .
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790996PMC
January 2021

Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy.

J Immunother Cancer 2020 10;8(2)

Department of Radiation Oncology, Emory University, Atlanta, Georgia, USA

Background: Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response.

Methods: We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells.

Results: We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8 T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a 'stem-like' CD8 T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8 T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8 and stem-like CD8 T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8 T-cells and stem-like CD8 T-cells in both the irradiated and unirradiated tumor.

Conclusions: These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8 T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.
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http://dx.doi.org/10.1136/jitc-2020-000867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542667PMC
October 2020

Influenza Immunization in the Context of Preexisting Immunity.

Cold Spring Harb Perspect Med 2020 Sep 28. Epub 2020 Sep 28.

Emory Vaccine Center and Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, Georgia 30322, USA.

Although we develop influenza immunity from an early age, it is insufficient to prevent future infection with antigenically novel strains. One proposed way to generate long-term protective immunity against a broad range of influenza virus strains is to boost responses to the conserved epitopes on the hemagglutinin, the major surface glycoprotein on the influenza virus. Influenza-specific humoral immunity comprises a large fraction of the overall immune memory in humans, and it has been long recognized that preexisting immunity to influenza shapes the response to subsequent influenza infections and vaccinations. However, the mechanisms by which preexisting immunity modulates the response to influenza vaccination are still not completely understood. Using a set of mathematical models, we explore several hypotheses that may contribute to diminished boosting of antibodies to conserved epitopes after repeated vaccinations.
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http://dx.doi.org/10.1101/cshperspect.a040964DOI Listing
September 2020

Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial.

Cancer 2020 12 28;126(23):5109-5113. Epub 2020 Sep 28.

Department of Radiation Oncology, Emory University, Atlanta, Georgia.

Background: Individuals of advanced age with comorbidities face a higher risk of death from coronavirus disease 2019 (COVID-19), especially once they are ventilator-dependent. Respiratory decline in patients with COVID-19 is precipitated by a lung-mediated aberrant immune cytokine storm. Low-dose lung radiation was used to treat pneumonia in the pre-antibiotic era. Radiation immunomodulatory effects may improve outcomes for select patients with COVID-19.

Methods: A single-institution trial evaluating the safety and efficacy of single-fraction, low-dose whole-lung radiation for patients with COVID-19 pneumonia is being performed for the first time. This report describes outcomes of a planned day 7 interim analysis. Eligible patients were hospitalized, had radiographic consolidation, required supplemental oxygen, and were clinically deteriorating.

Results: Of 9 patients screened, 5 were treated with whole-lung radiation on April 24 until April 28 2020, and they were followed for a minimum of 7 days. The median age was 90 years (range, 64-94 years), and 4 were nursing home residents with multiple comorbidities. Within 24 hours of radiation, 3 patients (60%) were weaned from supplemental oxygen to ambient air, 4 (80%) exhibited radiographic improvement, and the median Glasgow Coma Scale score improved from 10 to 14. A fourth patient (80% overall recovery) was weaned from oxygen at hour 96. The mean time to clinical recovery was 35 hours. There were no acute toxicities.

Conclusions: In a pilot trial of 5 oxygen-dependent elderly patients with COVID-19 pneumonia, low-dose whole-lung radiation led to rapid improvements in clinical status, encephalopathy, and radiographic consolidation without acute toxicity. Low-dose whole-lung radiation appears to be safe, shows early promise of efficacy, and warrants further study.

Lay Summary: Researchers at Emory University report preliminary safety outcomes for patients treated with low-dose lung irradiation for coronavirus disease 2019 (COVID-19) pneumonia. Five residents of nursing or group homes were hospitalized after testing positive for COVID-19. Each had pneumonia visible on a chest x-ray, required supplemental oxygen, and experienced a clinical decline in mental status or in work of breathing or a prolonged or escalating supplemental oxygen requirement. A single treatment of low-dose (1.5-Gy) radiation to both lungs was delivered over the course of 10 to 15 minutes. There was no acute toxicity attributable to radiation therapy. Within 24 hours, 4 patients had rapidly improved breathing, and they recovered to room air at an average of 1.5 days (range, 3-96 hours). Three were discharged at a mean time of 12 days, and 1 was preparing for discharge. Blood tests and repeat imaging confirm that low-dose whole-lung radiation treatment appears safe for COVID-19 pneumonia. Further trials are warranted.
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http://dx.doi.org/10.1002/cncr.33130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748390PMC
December 2020

Characteristics of Ebola Virus Disease Survivor Blood and Semen in Liberia: Serology and RT-PCR.

Clin Infect Dis 2020 Sep 7. Epub 2020 Sep 7.

Division of High-Consequence Pathogens and Pathology, National Center, for Emerging and Zoonotic Infectious Diseases, CDC.

Introduction: Ebola virus (EBOV), species Zaire ebolavirus, may persist in the semen of male survivors of Ebola Virus Disease (EVD). We conducted a study of male survivors of the 2014-2016 EVD outbreak in Liberia and evaluated their immune responses to EBOV. We report here findings from the serologic testing of blood for EBOV-specific antibodies, molecular testing for EBOV in blood and semen, and serologic testing of peripheral blood mononuclear cells (PBMCs) in a subset of study participants.

Methods: We tested for EBOV RNA in blood by qRT-PCR, and for anti-EBOV-specific IgM and IgG antibodies by enzyme-linked immunosorbent assay (ELISA) for 126 study participants. We performed peripheral blood mononuclear cell (PBMC) analysis on a subgroup of 26 IgG-negative participants.

Results: All 126 participants tested negative for EBOV RNA in blood by qRT-PCR. The blood of 26 participants tested negative for EBOV-specific IgG antibodies by ELISA. PBMCs were collected from 23/26 EBOV IgG-negative participants. Of these, 1/23 participants had PBMCs which produced anti-EBOV-specific IgG antibodies upon stimulation with EBOV-specific GP and NP antigens.

Discussion: The blood of EVD survivors, collected when they did not have symptoms meeting the case definition for acute or relapsed EVD, is unlikely to pose a risk for EBOV transmission. We identified one IgM/IgG negative participant who had PBMCs which produced anti-EBOV-specific antibodies upon stimulation. Immunogenicity following acute EBOV infection may exist along a spectrum and absence of antibody response should not be exclusionary in determining an individual's status as a survivor of EVD.
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http://dx.doi.org/10.1093/cid/ciaa1331DOI Listing
September 2020

Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients.

Cell Rep Med 2020 Jun 8;1(3):100040. Epub 2020 Jun 8.

Center for Childhood Infections and Vaccines; Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, GA 30322, USA.

SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
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http://dx.doi.org/10.1016/j.xcrm.2020.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276302PMC
June 2020

Influenza vaccine-induced human bone marrow plasma cells decline within a year after vaccination.

Science 2020 10 13;370(6513):237-241. Epub 2020 Aug 13.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.

A universal vaccine against influenza would ideally generate protective immune responses that are not only broadly reactive against multiple influenza strains but also long-lasting. Because long-term serum antibody levels are maintained by bone marrow plasma cells (BMPCs), we investigated the production and maintenance of these cells after influenza vaccination. We found increased numbers of influenza-specific BMPCs 4 weeks after immunization with the seasonal inactivated influenza vaccine, but numbers returned to near their prevaccination levels after 1 year. This decline was driven by the loss of BMPCs induced by the vaccine, whereas preexisting BMPCs were maintained. Our results suggest that most BMPCs generated by influenza vaccination in adults are short-lived. Designing strategies to enhance their persistence will be a key challenge for the next generation of influenza vaccines.
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http://dx.doi.org/10.1126/science.aaz8432DOI Listing
October 2020

T Cell Receptor Diversity and Lineage Relationship between Virus-Specific CD8 T Cell Subsets during Chronic Lymphocytic Choriomeningitis Virus Infection.

J Virol 2020 09 29;94(20). Epub 2020 Sep 29.

Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA

Recent studies on chronic viral infections have defined a novel programmed cell death 1-positive (PD-1) T cell factor 1-positive (TCF1) stem-like CD8 T cell subset that gives rise to the terminally differentiated exhausted CD8 T cells. In this study, we performed T cell receptor beta (TCRβ) sequencing of virus-specific CD8 T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection to examine the TCR diversity and lineage relationship of these two functionally distinct subsets. We found that >95% of the TCR repertoire of the exhausted CD8 T cell subset was shared with the stem-like CD8 T cells. The TCR repertoires of both CD8 T cell subsets were composed mostly of a few dominant clonotypes, but there was slightly more breadth and diversity in the stem-like CD8 T cells than their exhausted counterpart (∼40 versus ∼15 GP33 clonotypes; ∼20 versus ∼7 GP276 clonotypes). Interestingly, the breadth of the TCR repertoire was broader during the early stages (day 8) of the chronic infection than the later stages (days 45 to 60), showing that there was a narrowing of the TCR repertoire during chronic infection (∼2-fold GP33 and GP276 stem-like subset; ∼10-fold GP33 and ∼5-fold GP276 exhausted subset). In contrast, during acute LCMV infection, the TCR repertoire was much broader in both GP33-specific effector (∼160 clonotypes) and memory CD8 T cells (∼160 clonotypes). Overall, our data demonstrate that the virus-specific CD8 T cell TCR repertoire is broad and remains stable after acute LCMV infection, but it contracts and is narrower during chronic infection. Our study also shows that the repertoire of the exhausted CD8 T cell subset is almost completely derived from the stem-like CD8 T cell subset during established chronic LCMV infection. CD8 TCR repertoires responding to chronic viral infections (HIV, hepatitis C virus [HCV], Epstein-Barr virus [EBV], and cytomegalovirus [CMV]) have limited breadth and diversity. How these repertoires change and are maintained throughout the chronic infection are unknown. We thus characterized the LCMV-specific CD8 TCR repertoires of stem-like and terminally exhausted subsets generated during chronic LCMV infections. During chronic LCMV infections, the repertoires started as diverse but became more clonal at the late time point. Further, the exhausted subset was composed of dominant clonotypes that were shared with the stem-like subset. Together, we demonstrate that the TCR repertoire contracts over time and is almost exclusively derived from the stem-like subset late during the persistent viral infection. Our data suggest that dominant clonotypes in the exhausted subset are derived from a diverse pool of stem-like clonotypes, which may be contributing to the clonality observed during chronic viral infections.
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http://dx.doi.org/10.1128/JVI.00935-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527051PMC
September 2020

Adjuvanted H5N1 influenza vaccine enhances both cross-reactive memory B cell and strain-specific naive B cell responses in humans.

Proc Natl Acad Sci U S A 2020 07 13;117(30):17957-17964. Epub 2020 Jul 13.

Emory Vaccine Center, School of Medicine, Emory University, Atlanta, GA 30322;

There is a need for improved influenza vaccines. In this study we compared the antibody responses in humans after vaccination with an AS03-adjuvanted versus nonadjuvanted H5N1 avian influenza virus inactivated vaccine. Healthy young adults received two doses of either formulation 3 wk apart. We found that AS03 significantly enhanced H5 hemagglutinin (HA)-specific plasmablast and antibody responses compared to the nonadjuvanted vaccine. Plasmablast response after the first immunization was exclusively directed to the conserved HA stem region and came from memory B cells. Monoclonal antibodies (mAbs) derived from these plasmablasts had high levels of somatic hypermutation (SHM) and recognized the HA stem region of multiple influenza virus subtypes. Second immunization induced a plasmablast response to the highly variable HA head region. mAbs derived from these plasmablasts exhibited minimal SHM (naive B cell origin) and largely recognized the HA head region of the immunizing H5N1 strain. Interestingly, the antibody response to H5 HA stem region was much lower after the second immunization, and this suppression was most likely due to blocking of these epitopes by stem-specific antibodies induced by the first immunization. Taken together, these findings show that an adjuvanted influenza vaccine can substantially increase antibody responses in humans by effectively recruiting preexisting memory B cells as well as naive B cells into the response. In addition, we show that high levels of preexisting antibody can have a negative effect on boosting. These findings have implications toward the development of a universal influenza vaccine.
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http://dx.doi.org/10.1073/pnas.1906613117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395544PMC
July 2020

Harnessing Activin A Adjuvanticity to Promote Antibody Responses to BG505 HIV Envelope Trimers.

Front Immunol 2020 16;11:1213. Epub 2020 Jun 16.

Scripps Center for HIV/AIDS Vaccine Immunogen Development (CHAVD), The Scripps Research Institute, La Jolla, CA, United States.

T follicular helper (T) cells are powerful regulators of affinity matured long-lived plasma cells. Eliciting protective, long-lasting antibody responses to achieve persistent immunity is the goal of most successful vaccines. Thus, there is potential in manipulating T cell responses. Herein, we describe an HIV vaccine development approach exploiting the cytokine activin A to improve antibody responses against recombinant HIV Envelope (Env) trimers in non-human primates. Administration of activin A improved the magnitude of Env-specific antibodies over time and promoted a significant increase in Env-specific plasma cells in the bone marrow. The boost in antibody responses was associated with reduced frequencies of T follicular regulatory (T) cells and increased germinal center T follicular helper (GC-T) to T cell ratios. Overall, these findings suggest that adjuvants inducing activin A production could potentially be incorporated in future rational design vaccine strategies aimed at improving germinal centers, long-lived plasma cells, and sustained antibody responses.
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http://dx.doi.org/10.3389/fimmu.2020.01213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308430PMC
April 2021

3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates.

Sci Immunol 2020 06;5(48)

Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, 954, Gatewood Road, Atlanta, GA, USA.

A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that adjuvanting an HIV-1 clade C 1086.C-derived gp140 immunogen (Env) with a novel synthetic Toll-like receptor (TLR)-7/8 agonist named 3M-052 formulated in poly(lactic--glycolic)acid or PLGA nanoparticles (NPs) or with alum, either alone or in combination with a TLR-4 agonist GLA, induces notably high and persistent (up to ~1 year) frequencies of Env-specific LLPCs in the BM and serum antibody responses in rhesus macaques. Up to 36 and 18% of Env-specific cells among total IgG-secreting BM-resident plasma cells were detected at peak and termination, respectively. In contrast, adjuvanting Env with alum or GLA in NP induced significantly lower (~<100-fold) LLPC and antibody responses. Immune responses induced by 3M-052 were also significantly higher than those induced by a combination of TLR-7/8 (R848) and TLR-4 (MPL) agonists. Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (T) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs.
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http://dx.doi.org/10.1126/sciimmunol.abb1025DOI Listing
June 2020

Exosome-Containing Preparations From Postirradiated Mouse Melanoma Cells Delay Melanoma Growth In Vivo by a Natural Killer Cell-Dependent Mechanism.

Int J Radiat Oncol Biol Phys 2020 09 17;108(1):104-114. Epub 2020 Jun 17.

Department of Radiation Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, Georgia. Electronic address:

Purpose: To investigate the ability of radiation to stimulate exosome release from melanoma cells and to characterize the resulting exosome-containing vesicle preparations for their ability to promote a host antitumor immune response.

Materials And Methods: Cultured B16F10 murine melanoma cells or tumors were irradiated, and secreted extracellular vesicles were isolated and characterized. The exosome-containing vesicle preparations were injected into fresh tumors in syngeneic mice, and tumor growth and infiltrating T cells and natural killer (NK) cells were characterized.

Results: Irradiation stimulated exosome release from B16F10 murine melanoma cells. Exosome preparations from irradiated cell culture supernatants were biologically active, as demonstrated by uptake into recipient cells and by the ability to induce dendritic cell maturation and activation in vitro. Intratumoral injection significantly delayed tumor growth in vivo, whereas injection of similar preparations from non irradiated cells had no effect. The antitumor effect was correlated to an increase in interferon gamma-producing tumor-infiltrating NK cells. Pretreatment of the host mice with anti-NK cell antibodies abolished the effect, whereas pretreatment with anti-CD8 T-cell antibodies did not.

Conclusion: Exosomes from irradiated cells, or synthetic mimics, might provide an effective strategy for potentiation of NK cell-mediated host antitumor immunity.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751005PMC
September 2020

Rapid generation of neutralizing antibody responses in COVID-19 patients.

medRxiv 2020 May 8. Epub 2020 May 8.

SARS-CoV-2 is currently causing a devastating pandemic and there is a pressing need to understand the dynamics, specificity, and neutralizing potency of the humoral immune response during acute infection. Herein, we report the dynamics of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in 44 COVID-19 patients. RBD-specific IgG responses were detectable in all patients 6 days after PCR confirmation. Using a clinical isolate of SARS-CoV-2, neutralizing antibody titers were also detectable in all patients 6 days after PCR confirmation. The magnitude of RBD-specific IgG binding titers correlated strongly with viral neutralization. In a clinical setting, the initial analysis of the dynamics of RBD-specific IgG titers was corroborated in a larger cohort of PCR-confirmed patients (n=231). These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines.
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http://dx.doi.org/10.1101/2020.05.03.20084442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274246PMC
May 2020

Persistence of Varicella-Zoster Virus-Specific Plasma Cells in Adult Human Bone Marrow following Childhood Vaccination.

J Virol 2020 06 16;94(13). Epub 2020 Jun 16.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA

Childhood immunization with the live-attenuated varicella-zoster virus (VZV) vaccine induces protective immune responses. Routine VZV vaccination started only 2 decades ago, and thus, there are few studies examining the longevity of vaccine-induced immunity. Here, we analyzed the quantity of VZV-specific plasma cells (PCs) and CD4 T cells in the bone marrow (BM) of healthy young adults ( = 15) following childhood VZV immunization. Long-lived BM resident plasma cells constitutively secrete antibodies, and we detected VZV-specific PCs in the BM of all subjects. Anti-VZV plasma antibody titers correlated positively with the number of VZV-specific BM PCs. Furthermore, we quantified the number of interferon gamma (IFN-γ)-producing CD4 T cells specific for VZV glycoprotein E and all other structural and nonstructural VZV proteins in both BM and blood (peripheral blood mononuclear cells [PBMCs]). The frequency of VZV-specific IFN-γ-producing CD4 T cells was significantly higher in PBMCs than BM. Our study shows that VZV-specific PCs and VZV-specific CD4 memory T cells persist up to 20 years after vaccination. These findings indicate that childhood VZV vaccination can elicit long-lived immune memory responses in the bone marrow. Childhood varicella-zoster virus (VZV) immunization induces immune memory responses that protect against primary VZV infection, chicken pox. In the United States, routine childhood VZV vaccination was introduced only 2 decades ago. Hence, there is limited information on the longevity of B and CD4 T cell memory, which are both important for protection. Here, we showed in 15 healthy young adults that VZV-specific B and CD4 T cell responses are detectable in bone marrow (BM) and blood up to 20 years after vaccination. Specifically, we measured antibody-secreting plasma cells in the BM and VZV-specific CD4 T cells in BM and blood. These findings suggest that childhood VZV vaccination induces long-lived immunity.
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http://dx.doi.org/10.1128/JVI.02127-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307153PMC
June 2020

Editorial: HIV and Cancer Immunotherapy: Similar Challenges and Converging Approaches.

Front Immunol 2020 31;11:519. Epub 2020 Mar 31.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, United States.

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http://dx.doi.org/10.3389/fimmu.2020.00519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138010PMC
March 2021

Immune checkpoint modulation enhances HIV-1 antibody induction.

Nat Commun 2020 02 19;11(1):948. Epub 2020 Feb 19.

Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, 27710, USA.

Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.
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http://dx.doi.org/10.1038/s41467-020-14670-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031230PMC
February 2020

PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection.

Proc Natl Acad Sci U S A 2020 02 7;117(8):4292-4299. Epub 2020 Feb 7.

Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;

The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection.
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http://dx.doi.org/10.1073/pnas.1917298117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049149PMC
February 2020

Minimal immune response to booster vaccination against Yellow Fever associated with pre-existing antibodies.

Vaccine 2020 02 31;38(9):2172-2182. Epub 2020 Jan 31.

Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland. Electronic address:

Ever since its development in the 1930's, the live-attenuated Yellow Fever virus vaccine YF-17D has been highly effective. Despite the increasing knowledge on the immune biology of the YF-17D vaccine, most studies have focused only on a few types of immune cells and pathways or mainly on the primary adaptive immune response to YF-17D vaccination. Here, we examined humoral, innate and adaptive cellular responses in a longitudinal YF-17D vaccination study in Switzerland, comparing both primary and booster vaccination. In contrast to the strong innate and adaptive immune response to the primary vaccination, we find that the response to boosting is much reduced. Our data show an inverse association of neutralizing antibodies at baseline with vaccine virus replication and with the immune response upon boosting. These results suggest that booster vaccination may not have major immunological effects when neutralizing antibodies are present. Importantly, our study population was healthy adults in a non-endemic country and ultimately booster vaccine requirement must be assessed based on additional epidemiological and public health considerations in endemic areas.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.045DOI Listing
February 2020

Regulation of T and B cell responses to chronic antigenic stimulation during Infection, autoimmunity and transplantation.

Immunol Rev 2019 11;292(1):5-8

Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.

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http://dx.doi.org/10.1111/imr.12836DOI Listing
November 2019

Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1 Stem-like CD8 T Cells during Chronic Infection.

Immunity 2019 12 3;51(6):1043-1058.e4. Epub 2019 Dec 3.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30033, USA. Electronic address:

T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1 Tcf-1 CD8 T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1 CD8 T cells initially differentiated into a transitory population of CD101Tim3 cells that later converted into CD101 Tim3 cells. Recently generated CD101Tim3 cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101Tim3 CD8 T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920571PMC
December 2019

Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood.

Proc Natl Acad Sci U S A 2019 09 3;116(38):19071-19076. Epub 2019 Sep 3.

Hope Clinic of the Emory Vaccine Center, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30030;

In the past decade, multiple mumps outbreaks have occurred in the United States, primarily in close-contact, high-density settings such as colleges, with a high attack rate among young adults, many of whom had the recommended 2 doses of mumps-measles-rubella (MMR) vaccine. Waning humoral immunity and the circulation of divergent wild-type mumps strains have been proposed as contributing factors to mumps resurgence. Blood samples from 71 healthy 18- to 23-year-old college students living in a non-outbreak area were assayed for antibodies and memory B cells (MBCs) to mumps, measles, and rubella. Seroprevalence rates of mumps, measles, and rubella determined by IgG enzyme-linked immunosorbent assay (ELISA) were 93, 93, and 100%, respectively. The index standard ratio indicated that the concentration of IgG was significantly lower for mumps than rubella. High IgG avidity to mumps Enders strain was detected in sera of 59/71 participants who had sufficient IgG levels. The frequency of circulating mumps-specific MBCs was 5 to 10 times lower than measles and rubella, and 10% of the participants had no detectable MBCs to mumps. Geometric mean neutralizing antibody titers (GMTs) by plaque reduction neutralization to the predominant circulating wild-type mumps strain (genotype G) were 6-fold lower than the GMTs against the Jeryl Lynn vaccine strain (genotype A). The majority of the participants (80%) received their second MMR vaccine ≥10 years prior to study participation. Additional efforts are needed to fully characterize B and T cell immune responses to mumps vaccine and to develop strategies to improve the quality and durability of vaccine-induced immunity.
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http://dx.doi.org/10.1073/pnas.1905570116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754597PMC
September 2019

The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

Mol Cell 2019 09 31;75(6):1229-1242.e5. Epub 2019 Jul 31.

Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address:

Interferon gamma (IFN-γ), critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired Ifng response, and compromised host defense. Insertion of a polyA signal ablated the Ifng-as1 full-length transcript and impaired host defense, while allowing proper chromatin structure. Transient knockdown of Ifng-as1 also reduced IFN-γ production. In humans, discordant expression of IFNG and IFNG-AS1 was evident in memory T cells, with high expression of this long non-coding RNA (lncRNA) and low expression of the cytokine. These results establish Ifng-as1 as an important regulator of Ifng expression, as a DNA element and transcribed RNA, involved in dynamic and cell state-specific responses to infection.
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http://dx.doi.org/10.1016/j.molcel.2019.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754279PMC
September 2019