A live (delta aroA) Aeromonas salmonicida vaccine for furunculosis preferentially stimulates T-cell responses relative to B-cell responses in rainbow trout (Oncorhynchus mykiss).

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.

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Immunization with Live Attenuated Influenza Viruses That Express Altered NS1 Proteins Results in Potent and Protective Memory CD8+ T-Cell Responses

Journal of Virology ◽

10.1128/jvi.01317-09 ◽

2009 ◽

Vol 84 (4) ◽

pp. 1847-1855 ◽

Cited By ~ 31

Author(s):

Scott N. Mueller ◽

William A. Langley ◽

Elena Carnero ◽

Adolfo García-Sastre ◽

Rafi Ahmed

Keyword(s):

Influenza Virus ◽

T Cell ◽

B Cell ◽

Protective Immunity ◽

T Cell Responses ◽

Influenza Viruses ◽

Wild Type Virus ◽

Virus Infections ◽

Cell Responses ◽

B Cell Responses

ABSTRACT The generation of vaccines that induce long-lived protective immunity against influenza virus infections remains a challenging goal. Ideally, vaccines should elicit effective humoral and cellular immunity to protect an individual from infection or disease. Cross-reactive T- and B-cell responses that are elicited by live virus infections may provide such broad protection. Optimal induction of T-cell responses involves the action of type I interferons (IFN-I). Influenza virus expressed nonstructural protein 1 (NS1) functions as an inhibitor of IFN-I and promotes viral growth. We wanted to examine the priming of CD8+ T-cell responses to influenza virus in the absence of this inhibition of IFN-I production. We generated recombinant mouse-adapted influenza A/PR/8/34 viruses with NS1 truncations and/or deletions that also express the gp33-41 epitope from lymphocytic choriomeningitis virus. Intranasal infection of mice with the attenuated viruses primed long-lived T- and B-cell responses despite significantly reduced viral replication in the lungs compared to wild-type virus. Antigen-specific CD8+ T cells expanded upon rechallenge and generated increased protective memory T-cell populations after boosting. These results show that live attenuated influenza viruses expressing truncated NS1 proteins can prime protective immunity and may have implications for the design of novel modified live influenza virus vaccines.

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TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses

The Journal of Immunology ◽

10.4049/jimmunol.178.4.2182 ◽

2007 ◽

Vol 178 (4) ◽

pp. 2182-2191 ◽

Cited By ~ 148

Author(s):

Alex K. Heer ◽

Abdijapar Shamshiev ◽

Alena Donda ◽

Satoshi Uematsu ◽

Shizuo Akira ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

T Cell Responses ◽

Influenza B ◽

Tlr Signaling ◽

Effector T Cell ◽

Cell Responses ◽

B Cell Responses

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Memory T-Cell Responses to Vibrio cholerae O1 Infection

Infection and Immunity ◽

10.1128/iai.00793-09 ◽

2009 ◽

Vol 77 (11) ◽

pp. 5090-5096 ◽

Cited By ~ 34

Author(s):

Ana A. Weil ◽

Mohammad Arifuzzaman ◽

Taufiqur R. Bhuiyan ◽

Regina C. LaRocque ◽

Aaron M. Harris ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

B Cell ◽

Vibrio Cholerae ◽

Protective Immunity ◽

T Cell Responses ◽

Memory B Cell ◽

Memory T Cell ◽

Cell Responses ◽

B Cell Responses

ABSTRACTVibrio choleraeO1 can cause diarrheal disease that may be life-threatening without treatment. Natural infection results in long-lasting protective immunity, but the role of T cells in this immune response has not been well characterized. In contrast, robust B-cell responses toV. choleraeinfection have been observed. In particular, memory B-cell responses to T-cell-dependent antigens persist for at least 1 year, whereas responses to lipopolysaccharide, a T-cell-independent antigen, wane more rapidly after infection. We hypothesize that protective immunity is mediated by anamnestic responses of memory B cells in the gut-associated lymphoid tissue, and T-cell responses may be required to generate and maintain durable memory B-cell responses. In this study, we examined B- and T-cell responses in patients with severeV. choleraeinfection. Using the flow cytometric assay of the specific cell-mediated immune response in activated whole blood, we measured antigen-specific T-cell responses usingV. choleraeantigens, including the toxin-coregulated pilus (TcpA), aV. choleraemembrane preparation, and theV. choleraecytolysin/hemolysin (VCC) protein. Our results show that memory T-cell responses develop by day 7 after infection, a time prior to and concurrent with the development of B-cell responses. This suggests that T-cell responses toV. choleraeantigens may be important for the generation and stability of memory B-cell responses. The T-cell proliferative response to VCC was of a higher magnitude than responses observed to otherV. choleraeantigens.

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Persistence of antibody and T cell responses to the Sinopharm/BBIBP-CorV vaccine in Sri Lankan individuals

10.1101/2021.10.14.21265030 ◽

2021 ◽

Author(s):

Chandima Jeewandara ◽

Inoka Aberathna ◽

Pradeep Pushpakumara ◽

Achala Kamaladasa ◽

Dinuka Guruge ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

B Cell ◽

Severe Disease ◽

Age Groups ◽

T Cell Responses ◽

Sri Lankan ◽

Memory B Cell ◽

Cell Responses ◽

B Cell Responses

Background: To determine the kinetics and persistence of immune responses following the Sinopharm/BBIBP-CorV, we investigated immune responses in a cohort of Sri Lankan individuals. Methods: SARS-CoV-2 specific total antibodies were measured in 20-to-39 year (n=61), 40-to-59-year and those >60 years of age (n=22) by ELISA, 12 weeks after the second dose of the vaccine. ACE2 receptor blocking antibodies (ACE2R-Ab), antibodies to the receptor binding domain (RBD) of the ancestral virus (WT) and variants of concern, were measured in a sub cohort. T cell responses and memory B cell responses were assessed by ELISpot assays. Results: 193/203 (95.07%) of individuals had detectable SARS-CoV-2 specific total antibodies, while 67/110 (60.9%) had ACE2R-Ab. 14.3% to 16.7% individuals in the 20 to 39 age groups had detectable antibodies to the RBD of the WT and VOC, while the positivity rates of those >60 years of age was <10%. 14/49 (28.6%) had IFNγ ELISpot responses to overlapping peptides of the spike protein, while memory B cell responses were detected in 9/20 to the S1 recombinant protein. The total antibody levels and ACE2R-Ab declined after 2 to 12 weeks from the second dose, while ex vivo T cell responses remained unchanged. The decline in ACE2R-Ab levels was significant among the 40 to 59 (p=0.0007) and ≥60 (p=0.005) age groups. Conclusions: Antibody responses declined in all age groups, especially in those >60 years, while T cell responses persisted. The effect of waning of immunity on hospitalization and severe disease should be assessed by long term efficacy studies.

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The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00525-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Leiqiong Gao ◽

Jing Zhou ◽

Sen Yang ◽

Lisha Wang ◽

Xiangyu Chen ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Adaptive Immunity ◽

Disease Severity ◽

Protective Immunity ◽

Rational Design ◽

T Cell Responses ◽

Cell Responses ◽

Asymptomatic Patients ◽

B Cell Responses

AbstractThe adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.

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The dichotomous and incomplete adaptive immunity in COVID-19

10.1101/2020.09.05.20187435 ◽

2020 ◽

Cited By ~ 1

Author(s):

Leiqiong Gao ◽

Jing Zhou ◽

Sen Yang ◽

Xiangyu Chen ◽

Yang Yang ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Adaptive Immunity ◽

Disease Severity ◽

Protective Immunity ◽

Rational Design ◽

T Cell Responses ◽

Cell Responses ◽

Asymptomatic Patients ◽

B Cell Responses

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is also not well studied. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 49 patients with other disease severity (mild, n=10, moderate, n=32, severe, n=7) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and long-term humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results therefore uncovered the protective immunity in asymptomatic patients and revealed the strikingly dichotomous and unbalanced humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of COVID-19 vaccines.

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Temporal associations of B and T cell immunity with robust vaccine responsiveness in a 16-week interval BNT162b2 regimen

10.1101/2021.12.18.473317 ◽

2021 ◽

Author(s):

Manon Nayrac ◽

Mathieu Dube ◽

Geremy Sannier ◽

Alexandre Nicolas ◽

Lorie Marchitto ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

T Cell Responses ◽

Cd4 T Cell ◽

Immune Memory ◽

Integrated Analysis ◽

Cell Responses ◽

Cell Immunity ◽

B Cell Responses ◽

Humoral Responses

Spacing of the BNT162b2 mRNA doses beyond 3 weeks raised concerns about vaccine efficacy. We longitudinally analyzed B cell, T cell and humoral responses to two BNT162b2 mRNA doses administered 16 weeks apart in 53 SARS-CoV-2 naive and previously-infected donors. This regimen elicited robust RBD-specific B cell responses whose kinetics differed between cohorts, the second dose leading to increased magnitude in naive participants only. While boosting did not increase magnitude of CD4+ T cell responses further compared to the first dose, unsupervised clustering analyses of single-cell features revealed phenotypic and functional shifts over time and between cohorts. Integrated analysis showed longitudinal immune component-specific associations, with early Thelper responses post-first dose correlating with B cell responses after the second dose, and memory Thelper generated between doses correlating with CD8 T cell responses after boosting. Therefore, boosting elicits a robust cellular recall response after the 16-week interval, indicating functional immune memory.

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