Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection

Abstract

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)–driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called “decimation,” of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I–driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell–intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell–mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell–based vaccination against persistent viral diseases.

Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host

“…6 M ). We and others have reported that LCMV-specific B cells undergo biased terminal differentiation into short-lived antibody-secreting cells, when triggered in the first 3 d after infection ( 79 , 82 – 84 ). This process is driven by IFN-I-driven inflammation and results in a substantial depletion of virus-specific B cells, termed “B cell decimation”.…”

“…We extended our assessment of KL25 BCR-expressing B cells in antiviral immune responses and included also the more commonly used KL25HL strain ( 79 , 82 – 84 ) as a B cell donor. KL25HL mice carry the KL25H knock-in allele in conjunction with a transgenic KL25 light chain, thus a similar genetic configuration as the independently generated BasL36 strain, but B cells of KL25HL mice bound GP1 at lower levels and less consistently than BasL36 B cells ( Fig.…”

An advanced comprehensive muti-cell-type-specific model for predicting anti-PD-1 therapeutic effect in melanoma

“…We observed heterogeneity in the distribution of transcription factors within exhausted T cells undergoing oxidative stress-induced cell death. The antigen-presenting function of B cells in the cellular immune process is crucial, despite their classification as nonclassical antigen-presenting cells 74 . We found that the B_CD74 subgroup, which possesses antigen-presenting ability, accounted for up to 20% (maximum proportion) of lymphocytes in the NPD-pre group, but was completely absent in the PD-pre group.…”

Multiantigen pan-sarbecovirus DNA vaccines generate protective T cell immune responses

“…When mice were exposed to S antigen after vaccination, CoVAX_MNS-induced CD4 + T cells accelerated the generation of class-switched IgG Abs specific for the incoming S. In vitro, these CD4 + T cells upregulated CD40L and produced TNF upon S peptide stimulation, demonstrating that vaccination elicited S-specific T helper type 1 (T H 1) cells, which explains class switching to IgG2c. The most likely scenario is that upon encountering the S, the S-specific CD4 + T cells, including T H 1 and, potentially, T follicular helper cells, are recruited to lymph nodes and promote a germinal center response, which involves interaction with naive, S-specific B cells to promote their activation and differentiation into Ab-secreting plasmablasts ( 73 ). Similarly, CoVAX_MNS-vaccinated mice exposed to full-length S had accelerated generation of CD8 + T cells specific for an S epitope not contained within the vaccine.…”