Maintenance of Broad Neutralising Antibodies and Memory B Cells 12 Months Post-Infection Is Predicted by SARS-CoV-2 Specific CD4+ T Cell Responses

Background The duration and magnitude of SARS-CoV-2 immunity after infection, especially with regard to the emergence of new variants of concern (VoC), remains unclear. Here, immune memory to primary infection and immunity to VoC was assessed in mild-COVID-19 convalescents one year after infection and in the absence of viral re-exposure or COVID-19 vaccination. Methods Serum and PBMC were collected from mild-COVID-19 convalescents at ~6 and 12 months after a COVID-19 positive PCR (n=43) and from healthy SARS-CoV-2-seronegative controls (n=15-40). Serum titers of RBD and Spike-specific Ig were quantified by ELISA. Virus neutralisation was assessed against homologous, pseudotyped virus and homologous and VoC live viruses. Frequencies of Spike and RBD-specific memory B cells were quantified by flow cytometry. Magnitude of memory T cell responses was quantified and phenotyped by activation-induced marker assay, while T cell functionality was assessed by intracellular cytokine staining using peptides specific to homologous Spike virus antigen and four VoC Spike antigens. Findings At 12 months after mild-COVID-19, >90% of convalescents remained seropositive for RBD-IgG and 88.9% had circulating RBD-specific memory B cells. Despite this, only 51.2% convalescents had serum neutralising activity against homologous live-SARS-CoV-2 virus, which decreased to 44.2% when tested against live B.1.1.7, 4.6% against B.1.351, 11.6% against P.1 and 16.2%, against B.1.617.2 VoC. Spike and non-Spike-specific T cells were detected in >50% of convalescents with frequency values higher for Spike antigen (95% CI, 0.29-0.68% in CD4+ and 0.11-0.35% in CD8+ T cells), compared to non-Spike antigens. Despite the high prevalence and maintenance of Spike-specific T cells in Spike 'high-responder' convalescents at 12 months, T cell functionality, measured by cytokine expression after stimulation with Spike epitopes corresponding to VoC was severely affected. Interpretations SARS-CoV-2 immunity is retained in a significant proportion of mild COVID-19 convalescents 12 months post-infection in the absence of re-exposure to the virus. Despite this, changes in the amino acid sequence of the Spike antigen that are present in current VoC result in virus evasion of neutralising antibodies, as well as evasion of functional T cell responses.

Download Full-text

B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice

Hepatology ◽

10.1002/hep.28001 ◽

2015 ◽

Vol 62 (5) ◽

pp. 1563-1575 ◽

Cited By ~ 34

Author(s):

Xiaoming Liu ◽

Xuechao Jiang ◽

Ronghua Liu ◽

Luman Wang ◽

Tingting Qian ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Autoimmune Hepatitis ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses ◽

Experimental Autoimmune

Download Full-text

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

Frontiers in Neurology ◽

10.3389/fneur.2020.607766 ◽

2020 ◽

Vol 11 ◽

Author(s):

Austin Negron ◽

Olaf Stüve ◽

Thomas G. Forsthuber

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Responses ◽

Memory B Cells ◽

Lymphoid Follicles ◽

Cell Responses ◽

B Cell Responses

While the contribution of autoreactive CD4+ T cells to the pathogenesis of Multiple Sclerosis (MS) is widely accepted, the advent of B cell-depleting monoclonal antibody (mAb) therapies has shed new light on the complex cellular mechanisms underlying MS pathogenesis. Evidence supports the involvement of B cells in both antibody-dependent and -independent capacities. T cell-dependent B cell responses originate and take shape in germinal centers (GCs), specialized microenvironments that regulate B cell activation and subsequent differentiation into antibody-secreting cells (ASCs) or memory B cells, a process for which CD4+ T cells, namely follicular T helper (TFH) cells, are indispensable. ASCs carry out their effector function primarily via secreted Ig but also through the secretion of both pro- and anti-inflammatory cytokines. Memory B cells, in addition to being capable of rapidly differentiating into ASCs, can function as potent antigen-presenting cells (APCs) to cognate memory CD4+ T cells. Aberrant B cell responses are prevented, at least in part, by follicular regulatory T (TFR) cells, which are key suppressors of GC-derived autoreactive B cell responses through the expression of inhibitory receptors and cytokines, such as CTLA4 and IL-10, respectively. Therefore, GCs represent a critical site of peripheral B cell tolerance, and their dysregulation has been implicated in the pathogenesis of several autoimmune diseases. In MS patients, the presence of GC-like leptomeningeal ectopic lymphoid follicles (eLFs) has prompted their investigation as potential sources of pathogenic B and T cell responses. This hypothesis is supported by elevated levels of CXCL13 and circulating TFH cells in the cerebrospinal fluid (CSF) of MS patients, both of which are required to initiate and maintain GC reactions. Additionally, eLFs in post-mortem MS patient samples are notably devoid of TFR cells. The ability of GCs to generate and perpetuate, but also regulate autoreactive B and T cell responses driving MS pathology makes them an attractive target for therapeutic intervention. In this review, we will summarize the evidence from both humans and animal models supporting B cells as drivers of MS, the role of GC-like eLFs in the pathogenesis of MS, and mechanisms controlling GC-derived autoreactive B cell responses in MS.

Download Full-text

Absence of memory B cells and unbalanced T cell responses in a C3 deficient patient

Molecular Immunology ◽

10.1016/j.molimm.2007.06.010 ◽

2007 ◽

Vol 44 (16) ◽

pp. 3910 ◽

Cited By ~ 1

Author(s):

A. Ghannam ◽

M. Pernollet ◽

J.-L. Fauquert ◽

N. Monnier ◽

D. Ponard ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

T Cell Responses ◽

Memory B Cells ◽

Cell Responses ◽

Deficient Patient

Download Full-text

IgE-Mediated Enhancement of CD4+ T Cell Responses in Mice Requires Antigen Presentation by CD11c+ Cells and Not by B Cells

PLoS ONE ◽

10.1371/journal.pone.0021760 ◽

2011 ◽

Vol 6 (7) ◽

pp. e21760 ◽

Cited By ~ 27

Author(s):

Frida Henningsson ◽

Zhoujie Ding ◽

Joakim S. Dahlin ◽

Marius Linkevicius ◽

Fredrik Carlsson ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Antigen Presentation ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses ◽

Ige Mediated

Download Full-text

CD4+ T cell responses in mice lacking MHC class II molecules specifically on B cells

European Journal of Immunology ◽

10.1002/(sici)1521-4141(199811)28:11<3763::aid-immu3763>3.0.co;2-d ◽

1998 ◽

Vol 28 (11) ◽

pp. 3763-3772 ◽

Cited By ~ 23

Author(s):

G. Stuart Williams ◽

Annette Oxenius ◽

Hans Hengartner ◽

Christophe Benoist ◽

Diane Mathis

Keyword(s):

T Cell ◽

B Cells ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Cd4 T Cell ◽

Cell Responses ◽

Mhc Class Ii Molecules

Download Full-text

B Cells: Programmers of CD4 T Cell Responses

Infectious Disorders - Drug Targets ◽

10.2174/187152612800564446 ◽

2012 ◽

Vol 12 (3) ◽

pp. 222-231 ◽

Cited By ~ 20

Author(s):

Tom A. Barr ◽

Mohini Gray ◽

David Gray

Keyword(s):

T Cell ◽

B Cells ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

Download Full-text

Cellular and Humoral Immunity to Ebola Zaire Glycoprotein and Viral Vector Proteins Following Immunization with Recombinant Vesicular Stomatitis Virus-Based Ebola Vaccine (rVSV∆G-EBOV-GP)

10.1101/2021.11.09.21266118 ◽

2021 ◽

Author(s):

Vanessa N Raabe ◽

Lilin Lai ◽

Juliet Morales ◽

Yongxian Xu ◽

Nadine Rouphael ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Vesicular Stomatitis Virus ◽

Matrix Protein ◽

T Cell Responses ◽

Memory B Cells ◽

Post Vaccination ◽

Cell Responses ◽

Vesicular Stomatitis ◽

Nucleoprotein N

While effective at preventing Zaire ebolavirus (EBOV) disease, cellular immunity to EBOV and vector-directed immunity elicited by the recombinant vesicular stomatitis virus expressing Ebola glycoprotein (rVSVΔG-EBOV-GP) vaccine remains poorly understood. Sera and peripheral blood mononuclear cells were collected from 32 participants enrolled in a prospective multicenter study [ClinicalTrials.gov NCT02788227] before vaccination and up to six months post-vaccination. IgM and IgG antibodies, IgG-producing memory B cells, and T cell reactivity to EBOV glycoprotein, vesicular stomatitis virus-Indiana strain (VSV-I) matrix protein, and VSV-I nucleoprotein were measured using ELISA, ELISpot, and intracellular cytokine staining, respectively. Eleven participants previously received a different investigational Ebola vaccine. All participants met positivity criteria for IgG antibodies to, and circulating IgG-producing memory B cells to, EBOV glycoprotein following rVSVΔG-EBOV-GP vaccination. Transient IgM and IgG antibody responses to VSV-I matrix protein (n=1/32 and n=0/32, respectively) and nucleoprotein (n=2/32 and n=1/32, respectively) were infrequently detected, as were IgG-producing memory B cells recognizing VSV-I matrix protein (n=3/31) and nucleoprotein (n=2/31). CD4+ and CD8+ T cell responses to EBOV glycoprotein were present in 15/32 and 19/32 participants at baseline and in 32/32 and 23/32 participants one month post-vaccination, respectively. CD4+ and CD8+ T cell responses to VSV-I matrix protein (n=17/32 and n=16/32, respectively) and VSV-I nucleoprotein (n=23/32 for both CD4+ and CD8+ responses) were common post-vaccination. T cell responses were predominantly mono-cytokine, except CD8+ responses to EBOV glycoprotein among heterologous Ebola vaccine-experienced participants and CD8+ responses to VSV-I nucleoprotein. Overall, rVSVΔG-EBOV-GP elicits robust humoral and memory B cell responses to EBOV glycoprotein in both Ebola vaccine-naïve and heterologous Ebola vaccine-experienced individuals and can generate vector-directed T cell immunity. Further research is needed to understand the significance of pre-existing vector-directed immunity on responses to booster doses of rVSVΔG-EBOV-GP and other rVSV-vectored vaccines.

Download Full-text

Immunity in Omicron SARS-CoV-2 breakthrough COVID-19 in vaccinated adults

10.1101/2022.01.13.22269213 ◽

2022 ◽

Author(s):

Hassen Kared ◽

Asia-Sophia Fumika Michaela Wolf ◽

Amin Alirezaylavasani ◽

Anthony Ravussin ◽

Guri Solum ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

De Novo ◽

T Cell Responses ◽

Affinity Maturation ◽

T Cell Response ◽

Memory B Cells ◽

Viral Escape ◽

Cell Responses

The new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-19, with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increased de novo memory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.

Download Full-text