Engagement of CD40 on B cells with CD40L is critical to Ag-specific B cell proliferation and differentiation into extrafollicular plasmablasts that can seed germinal centers (GCs) and drive humoral immune responses. The stability of CD40L mRNA is mediated by RNA binding complexes composed of the polypyrimidine tract–binding protein (PTBP1) to a site on the 3′ untranslated region of the mRNA. In this Top Read, Narayanan et al. (p. 2552) evaluated the effect of CD40L mRNA expression on humoral immunity by engineering a mouse that was deficient in the CD40L stability element (CD40LΔ5). This mutation resulted in expression of CD40L on CD4 T cells at 60% of wild-type levels and dramatically reduced levels of T-dependent Abs. CD40LΔ5 mice also had a loss of GL7+ GC B cells and a disorganized GC. In addition, fewer plasmablasts and early memory B cell precursors were observed as a fraction of GL7+ B cells. Somatic hypermutation was not significantly affected, but fewer high-affinity Abs were detected. These data suggest that GC B cell differentiation is sensitive to CD40L signaling levels, which is closely linked to CD40L mRNA stability.

Infection with SARS-CoV-2, the β-coronavirus that causes COVID-19, is associated with early expansion of plasmablasts followed by formation of SARS-CoV-2–specific memory B cells. In this Top Read, Mantus et al. (p. 2605) evaluated SARS-CoV-2–specific B cell population dynamics in a cohort of hospitalized COVID-19 patients. CD19+ cell subsets were sampled in patients at different time points from 3 to 57 d postsymptom onset and were compared with healthy controls. The researchers observed dramatic expansion of the B cell compartment 2–3 wk following symptom onset. Plasmablasts expanded within the first week and remained elevated, but memory B cells decreased in symptomatic patients. SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells were detected 8–14 d postsymptom onset and showed upregulation of the activation marker CD71. In addition, IgG and IgA Abs specific to viral RBD, spike protein, or nucleoprotein peaked at 3 wk postsymptom onset. RBD Abtiters correlated directly with serum neutralization activity, and depletion of RBD-specific Abs decreased serum neutralization activity for most individuals. These findings provide further insight into critical B cell responses to SARS-CoV-2 infection.

CD4 T cells in the gut of people living with HIV (PLWH) are viral reservoirs that persist even during antiretroviral therapy (ART). T cell gut homing is driven by retinoic acid (RA), a metabolite produced by DCs with RA-synthesizing activity (RALDH). In this Top Read, Cattin et al. (p. 2638) evaluated the role of bacterial/fungal pathogens in inducing RALDH activity in DCs and promoting HIV reservoir establishment or outgrowth. DCs derived from CD16+ monocyte-derived DCs (MDDCs) showed greater RALDH activity compared with CD16 MDDCs in the presence of Staphylococcus aureus–reactive T cells from PLWH. MDDCs exposed to S. aureus lysates, zymosan, or LPS, but not CMV lysates, also showed a dramatic increase in RALDH activity. In addition, MDDCs exposed to S. aureus lysate promoted HIV infection of CD4 T cells in trans from PLWH in an RA/RALDH manner. Moreover, S. aureus– or zymosan-loaded MDDCs induced HIV outgrowth of S. aureus– or zymosan-specific CD4 T cells from ART-treated PLWH. These observations indicate that bacterial and fungal pathogens may play a critical role in the establishment and/or outgrowth of HIV reservoirs via an RA/RALDH-dependent mechanism.

In this Top Read, Alborzian Deh Sheikh et al. (p. 2544) demonstrate that protein tyrosine phosphatase SHP-1, not CD45, is required for ligand-mediated regulation of CD22. CD22 can bind to ɑ2,6 sialic acid–containing molecules such as CD22, CD45, and IgM. Specific disruption of CD22 binding to α2,6 sialic acid enhances its phosphorylation during BCR ligation in wild-type and CD45−/− B cells but not SHP-1 loss-of-function mutant B cells. These results suggest that although CD45 contributes to optimal CD22-mediated BCR signaling inhibition, CD22 may serve as its own endogenous ligand to enhance BCR-ligation–induced signaling through SHP-1 dephosphorylation.