scholarly journals SARS-CoV-2 infection induces germinal center responses with robust stimulation of CD4 T follicular helper cells in rhesus macaques

2020 ◽  
Author(s):  
Sonny R. Elizaldi ◽  
Yashavanth Shaan Lakshmanappa ◽  
Jamin W. Roh ◽  
Brian A. Schmidt ◽  
Timothy D. Carroll ◽  
...  
Keyword(s):  
Germinal Center ◽  
Protective Immunity ◽  
Viral Infections ◽  
Rhesus Macaques ◽  
Igg Antibodies ◽  
Cell Responses ◽  
Follicular Helper ◽  
Early Appearance ◽  
Iga Antibodies ◽  
Stimulation Of

ABSTRACTCD4 T follicular helper (Tfh) cells are important for the generation of long-lasting and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that, following infection with SARS-CoV-2, adult rhesus macaques exhibited transient accumulation of activated, proliferating Tfh cells in their peripheral blood on a transitory basis. The CD4 helper cell responses were skewed predominantly toward a Th1 response in blood, lung, and lymph nodes, reflective of the interferon-rich cytokine environment following infection. We also observed the generation of germinal center Tfh cells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies but delayed or absent IgA antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.

scholarly journals SARS-CoV-2 infection induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

2020 ◽  
Author(s):  
Sonny Elizaldi ◽  
Yashavanth Shaan Lakshmanappa ◽  
Jamin Roh ◽  
Brian Schmidt ◽  
Timothy Carroll ◽  
...  
Keyword(s):  
Germinal Center ◽  
Protective Immunity ◽  
Viral Infections ◽  
Rhesus Macaques ◽  
Helper Cell ◽  
Igg Antibodies ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
Follicular Helper ◽  
T Follicular Helper Cell

Abstract CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that SARS-CoV-2 infection resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses were skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. We observed the generation of germinal center Tfh cells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.

scholarly journals SARS-CoV-2 induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yashavanth Shaan Lakshmanappa ◽  
Sonny R. Elizaldi ◽  
Jamin W. Roh ◽  
Brian A. Schmidt ◽  
Timothy D. Carroll ◽  
...  
Keyword(s):  
Germinal Center ◽  
Viral Infections ◽  
Rhesus Macaques ◽  
Helper Cell ◽  
Nucleocapsid Proteins ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
Follicular Helper ◽  
T Follicular Helper Cell ◽  
Induced Immunity

AbstractCD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center (GC) response is an important question as we investigate vaccine induced immunity against COVID-19. Here, we report that SARS-CoV-2 infection in rhesus macaques, either infused with convalescent plasma, normal plasma, or receiving no infusion, resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. SARS-CoV-2 Infection induced GC Tfh cells specific for the SARS-CoV-2 spike and nucleocapsid proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Collectively, the data show induction of GC responses in a rhesus model of mild COVID-19.

scholarly journals Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses

2018 ◽  
Vol 215 (6) ◽  
pp. 1571-1588 ◽  
Author(s):  
Norbert Pardi ◽  
Michael J. Hogan ◽  
Martin S. Naradikian ◽  
Kaela Parkhouse ◽  
Derek W. Cain ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Modified Nucleosides ◽  
Vaccine Platform ◽  
Intradermal Vaccination ◽  
Cell Responses ◽  
Follicular Helper

T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.

scholarly journals Marginal zone SIGN-R1+macrophages are essential for the maturation of germinal center B cells in the spleen

2020 ◽  
Vol 117 (22) ◽  
pp. 12295-12305
Author(s):  
Gabriela Pirgova ◽  
Anne Chauveau ◽  
Andrew J. MacLean ◽  
Jason G. Cyster ◽  
Tal I. Arnon
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Cell Responses ◽  
Functional Specification ◽  
Follicular Helper ◽  
Initial Activation ◽  
Macrophage Subsets ◽  
Specific Contribution

The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+macrophages, DCIR2+dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+macrophages to the spleen corrected positioning of DCIR2+DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.

scholarly journals Repeated In Vivo Stimulation of T and B Cell Responses in Old Mice Generates Protective Immunity against Lethal West Nile Virus Encephalitis

2011 ◽  
Vol 186 (7) ◽  
pp. 3882-3891 ◽  
Author(s):  
Jennifer L. Uhrlaub ◽  
James D. Brien ◽  
Douglas G. Widman ◽  
Peter W. Mason ◽  
Janko Nikolich-Žugich
Keyword(s):  
West Nile Virus ◽  
B Cell ◽  
Protective Immunity ◽  
West Nile ◽  
Virus Encephalitis ◽  
Cell Responses ◽  
West Nile Virus Encephalitis ◽  
Old Mice ◽  
Stimulation Of

scholarly journals Follicular Helper NKT Cells Induce Limited B Cell Responses and Germinal Center Formation in the Absence of CD4+ T Cell Help

2012 ◽  
Vol 188 (7) ◽  
pp. 3217-3222 ◽  
Author(s):  
Elena Tonti ◽  
Maya Fedeli ◽  
Anna Napolitano ◽  
Matteo Iannacone ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Germinal Center ◽  
Nkt Cells ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Follicular Helper ◽  
Cd4 T Cell Help ◽  
T Cell Help ◽  
Germinal Center Formation

scholarly journals Germinal Center B Cell and T Follicular Helper Cell Responses to Viral Vector and Protein-in-Adjuvant Vaccines

2016 ◽  
Vol 197 (4) ◽  
pp. 1242-1251 ◽  
Author(s):  
Chuan Wang ◽  
Matthew Hart ◽  
Cecilia Chui ◽  
Augustine Ajuogu ◽  
Iona J. Brian ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Viral Vector ◽  
Helper Cell ◽  
Cell Responses ◽  
Follicular Helper ◽  
Germinal Center B Cell ◽  
T Follicular Helper Cell

scholarly journals Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells

2017 ◽  
Vol 214 (5) ◽  
pp. 1259-1267 ◽  
Author(s):  
Nike J. Kräutler ◽  
Dan Suan ◽  
Danyal Butt ◽  
Katherine Bourne ◽  
Jana R. Hermes ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Protective Immunity ◽  
Plasma Cells ◽  
Discrete Subset ◽  
Autoantibody Production ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper

Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.

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