Affinity-independent memory B cell origin of the early antibody-secreting cell response in naive individuals upon SARS-CoV-2 vaccination.

Memory B cells (MBCs) formed over the individual's lifetime constitute nearly half of the circulating B cell repertoire in humans. These pre-existing MBCs dominate recall responses to their cognate antigens, but how they respond to recognition of novel antigens is not well understood. Here, we tracked the origin and followed the differentiation paths of MBCs in the early anti-spike (S) response to mRNA vaccination in SARS-CoV-2-naive individuals on single-cell and monoclonal antibody levels. Pre-existing, highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody-secreting cells (ASCs). By contrast, and despite similar levels of S reactivity, naive B cells showed strong signs of antibody affinity maturation before differentiating into MBCs and ASCs. Thus, pre-existing human MBCs differentiate into ASCs in response to novel antigens, but the quality of the humoral and cellular anti-S response improved through the clonal selection and affinity maturation of naive precursors.

VSTM5 is a novel immune checkpoint that promotes oral tolerance of cell-mediated and antibody responses.

The V-set and transmembrane domain-containing protein (VSTM) family is a newly discovered immunoglobulin (Ig) superfamily that shares structural similarities with the B7-like transmembrane proteins. Although most VSTM5 members have been reported to exert immune-related functions, VSTM5 has been described as a regulator of neuronal morphogenesis and migration in the brain. Based on its close phylogenetic relationship with two immune checkpoints, VISTA and TIGIT, we investigated the potential role of VSTM5 in T-cell immune responses. VSTM5.Ig inhibits T-cell proliferation and cytokine production, induces T-cell apoptosis, and promotes the generation of regulatory T cells (Tregs) in in vitro T-cell assays. VSTM5 also contributes to the maintenance of T-cell anergy in vitro. Similarly, serum VSTM5.Ig produced using a recombinant plasmid in ovalbumin (OVA)-immunized mice inhibits both naive and effector T-cell immune responses. In addition, VSTM5.Ig enhances oral tolerance of cell-mediated and antibody responses in OVA-fed mice by inducing Tregs and T-cell clonal deletion. Consequently, our findings suggest that VSTM5 is a novel immune checkpoint that could be used to improve the therapeutic efficacy of tolerance-based therapies for autoimmune diseases.

Molecular and functional properties of human Plasmodium falciparum CSP C-terminus antibodies.

Human monoclonal antibodies (mAbs) against the central repeat and junction domain of Plasmodium falciparum circumsporozoite protein (PfCSP) have been studied extensively to guide malaria vaccine design compared to antibodies against the PfCSP C terminus. Here, we describe the molecular characteristics and protective potential of 73 germline and mutated human mAbs against the highly immunogenic PfCSP C-terminal domain. Two mAbs recognized linear epitopes in the C-terminal linker with sequence similarity to repeat and junction motifs, whereas all others targeted conformational epitopes in the α-thrombospondin repeat (α-TSR) domain. Specificity for the polymorphic Th2R/Th3R but not the conserved RII+/CS.T3 region in the α-TSR was associated with IGHV3-21/IGVL3-21 or IGLV3-1 gene usage. Although the C terminus specific mAbs showed signs of more efficient affinity maturation and class-switching compared to anti-repeat mAbs, live sporozoite binding and inhibitory activity was limited to a single C-linker reactive mAb with cross-reactivity to the central repeat and junction. The data provide novel insights in the human anti-C-linker and anti-α-TSR antibody response that support exclusion of the PfCSP C terminus from malaria vaccine designs.