Publications by authors named "Catherine Nakao"

7 Publications

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Immunological memory to SARS-CoV-2 assessed for up to eight months after infection.

bioRxiv 2020 Dec 18. Epub 2020 Dec 18.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4 T cells and CD8 T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4 T cell, and CD8 T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
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http://dx.doi.org/10.1101/2020.11.15.383323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805444PMC
December 2020

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.

Science 2021 02 6;371(6529). Epub 2021 Jan 6.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.

Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4 T cells and CD8 T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4 T cell, and CD8 T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
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http://dx.doi.org/10.1126/science.abf4063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919858PMC
February 2021

Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers.

J Exp Med 2021 Feb;218(2)

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA.

Immunodominance to nonneutralizing epitopes is a roadblock in designing vaccines against several diseases of high interest. One hypothetical possibility is that limited CD4 T cell help to B cells in a normal germinal center (GC) response results in selective recruitment of abundant, immunodominant B cells. This is a central issue in HIV envelope glycoprotein (Env) vaccine designs, because precursors to broadly neutralizing epitopes are rare. Here, we sought to elucidate whether modulating the quantity of T cell help can influence recruitment and competition of broadly neutralizing antibody precursor B cells at a physiological precursor frequency in response to Env trimer immunization. To do so, two new Env-specific CD4 transgenic (Tg) T cell receptor (TCR) mouse lines were generated, carrying TCR pairs derived from Env-protein immunization. Our results suggest that CD4 T cell help quantitatively regulates early recruitment of rare B cells to GCs.
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http://dx.doi.org/10.1084/jem.20201254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769167PMC
February 2021

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.

Cell 2019 05 9;177(5):1153-1171.e28. Epub 2019 May 9.

Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address:

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.
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http://dx.doi.org/10.1016/j.cell.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619430PMC
May 2019

Human Monocyte Heterogeneity as Revealed by High-Dimensional Mass Cytometry.

Arterioscler Thromb Vasc Biol 2019 01;39(1):25-36

From the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA (A.A.J.H., H.Q.D., G.D.T., P.M., A.B., C.S.N., C.C.H.).

Objective- Three distinct human monocyte subsets have been identified based on the surface marker expression of CD14 and CD16. We hypothesized that monocytes were likely more heterogeneous in composition. Approach and Results- We used the high dimensionality of mass cytometry together with the FlowSOM clustering algorithm to accurately identify and define monocyte subsets in blood of healthy human subjects and those with coronary artery disease (CAD). To study the behavior and functionality of the newly defined monocyte subsets, we performed RNA sequencing, transwell migration, and efferocytosis assays. Here, we identify 8 human monocyte subsets based on their surface marker phenotype. We found that 3 of these subsets fall within the CD16 nonclassical monocyte population and 4 subsets belong to the CD14 classical monocytes, illustrating significant monocyte heterogeneity in humans. As nonclassical monocytes are important in modulating atherosclerosis in mice, we studied the functions of our 3 newly identified nonclassical monocytes in subjects with CAD. We found a marked expansion of a SlanCXCR6 nonclassical monocyte subset in CAD subjects, which was positively correlated with CAD severity. This nonclassical subset can migrate towards CXCL16 and shows an increased efferocytosis capacity, indicating it may play an atheroprotective role. Conclusions- Our data demonstrate that human nonclassical monocytes are a heterogeneous population, existing of several subsets with functional differences. These subsets have changed frequencies in the setting of severe CAD. Understanding how these newly identified subsets modulate CAD will be important for CAD-based therapies that target myeloid cells.
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http://dx.doi.org/10.1161/ATVBAHA.118.311022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697379PMC
January 2019

Human Blood Monocyte Subsets: A New Gating Strategy Defined Using Cell Surface Markers Identified by Mass Cytometry.

Arterioscler Thromb Vasc Biol 2017 08 8;37(8):1548-1558. Epub 2017 Jun 8.

From the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA (G.D.T., A.A.J.H., C.N., P.M., C.C.H.); and Division of Cardiology and Robert M. Berne Cardiovascular Center, University of Virginia, Charlottesville (A.M.T., C.M., A.T.N., C.A.M.).

Objective: Human monocyte subsets are defined as classical (CD14CD16), intermediate (CD14CD16), and nonclassical (CD14CD16). Alterations in monocyte subset frequencies are associated with clinical outcomes, including cardiovascular disease, in which circulating intermediate monocytes independently predict cardiovascular events. However, delineating mechanisms of monocyte function is hampered by inconsistent results among studies.

Approach And Results: We use cytometry by time-of-flight mass cytometry to profile human monocytes using a panel of 36 cell surface markers. Using the dimensionality reduction approach visual interactive stochastic neighbor embedding (viSNE), we define monocytes by incorporating all cell surface markers simultaneously. Using viSNE, we find that although classical monocytes are defined with high purity using CD14 and CD16, intermediate and nonclassical monocytes defined using CD14 and CD16 alone are frequently contaminated, with average intermediate and nonclassical monocyte purity of ≈86.0% and 87.2%, respectively. To improve the monocyte purity, we devised a new gating scheme that takes advantage of the shared coexpression of cell surface markers on each subset. In addition to CD14 and CD16, CCR2, CD36, HLA-DR, and CD11c are the most informative markers that discriminate among the 3 monocyte populations. Using these additional markers as filters, our revised gating scheme increases the purity of both intermediate and nonclassical monocyte subsets to 98.8% and 99.1%, respectively. We demonstrate the use of this new gating scheme using conventional flow cytometry of peripheral blood mononuclear cells from subjects with cardiovascular disease.

Conclusions: Using cytometry by time-of-flight mass cytometry, we have identified a small panel of surface markers that can significantly improve monocyte subset identification and purity in flow cytometry. Such a revised gating scheme will be useful for clinical studies of monocyte function in human cardiovascular disease.
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http://dx.doi.org/10.1161/ATVBAHA.117.309145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828170PMC
August 2017