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

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.

Evolution of antigen-specific follicular helper T cell transcriptional programs across effector function and through to memory

Understanding how follicular helper T cells (TFH) regulate the specialization, maturation, and differentiation of adaptive B cell immunity is crucial for developing durable high-affinity immune protection. Using indexed-single cell molecular strategies, we reveal a skewed intra-clonal assortment of higher affinity TCR and the distinct molecular programming of the localized TFH compartment compared to emigrant conventional effector TH (ETH) cells. We find a temporal shift in BCR class switch which permits identification of inflammatory and anti-inflammatory modules of transcriptional programming that subspecialize TFH function before and during the germinal center (GC) reaction. Late collapse of this local primary GC reaction reveals a persistent post-GC TFH population which discloses a putative memory TFH program. These studies define specialized antigen-specific TFH transcriptional programs that progressively direct class-specific evolution of high-affinity B cell immunity and uncover the transcriptional program of a memory TFH population as the regulators of antigen recall.Graphical AbstractSummaryDistinct inflammatory and anti-inflammatory antigen-specific TFH transcriptional programs regulate class-specific B cell maturation.Highlights- Skewed intra-clonal assortment of high affinity TCR into the TFH compartment- Significant temporal delay in anti-inflammatory IgG1 production- Inflammatory and anti-inflammatory transcriptional modules subspecialize TFH- Late GC collapse reveals a persisting post-GC putative memory TFH compartment

No substantial pre-existing B cell immunity against SARS-CoV-2 in healthy adults

SummaryPre-existing immunity against SARS-CoV-2 may have critical implications for our understanding of COVID-19 susceptibility and severity. Various studies recently provided evidence of pre-existing T cell immunity against SARS-CoV-2 in unexposed individuals. In contrast, the presence and clinical relevance of a pre-existing B cell immunity remains to be fully elucidated. Here, we provide a detailed analysis of the B cell response to SARS-CoV-2 in unexposed individuals. To this end, we extensively investigated the memory B cell response to SARS-CoV-2 in 150 adults sampled pre-pandemically. Comprehensive screening of donor plasma and purified IgG samples for binding and neutralization in various functional assays revealed no substantial activity against SARS-CoV-2 but broad reactivity to endemic betacoronaviruses. Moreover, we analyzed antibody sequences of 8,174 putatively SARS-CoV-2-reactive B cells on a single cell level and generated and tested 158 monoclonal antibodies. None of the isolated antibodies displayed relevant binding or neutralizing activity against SARS-CoV-2. Taken together, our results show no evidence of relevant pre-existing antibody and B cell immunity against SARS-CoV-2 in unexposed adults.