Immune Complex Cycling in Follicular DCs See article p. 1436

Epigenetics of Memory B Cell Reactivation See article p. 1493

Zinc Fingers Point to Plasma Cell Differentiation See article p. 1515

Helminths Promote Anti-Inflammatory Trained Immunity See article p. 1618

IFN-γ Boosts Monocyte IL-12 Response See article p. 1642

Costimulation Blockade of T Cells in Transplantation See article p. 1668

Many studies have shown that parasitic infections can suppress autoimmune diseases. In this Top Read, Cunningham et al. (p. 1618) show that treating mice with Fasciola hepatica excretory-secretory product (FHES) results in anti-inflammatory trained immunity. Mice injected with FHES had higher numbers of anti-inflammatory monocytes and macrophages. Compared with control mice, stimulated bone marrow–derived macrophages from FHES-treated mice had increased production of IL-1R agonist and IL-10, along with decreased levels of IL-1β secretion, which lasted 18 mo following FHES treatment. Pretreating mice with FHES prior to induction of autoimmune encephalomyelitis (EAE) resulted in lower numbers of infiltrating CD4 T cells producing IL-17 and IFN-γ and failed to develop into the severe disease observed in mock-treated mice. However, transfer of T cells from FHES-treated mice into EAE animals failed to mitigate disease. FHES treatment mediated epigenetic and metabolic changes in the bone marrow, resulting in preferential differentiation of myeloid cells. Bone marrow from FHES-treated mice transferred to EAE mice delayed disease onset and severity. Together, these data provide insight into how helminths may promote long-lived anti-inflammatory trained immunity by modulating stem cells.

Molecules that block costimulatory pathways, such as the CTLA4-Ig fusion protein, are being explored as alternative treatments to maintain immunosuppression in kidney transplantation. In some cases, costimulation blockade (CoB) can result in acute rejection, mediated in part by T cells resistant to CoB. In this Top Read, Shaw et al. (p. 1668) characterize a subset of CoB-resistant CD57+PD1 CD4 T cells to understand their role in transplant rejection. CD57+PD1 CD4 T cells can be found in end-stage renal disease patients prior to transplantation, and the frequency of this subset correlated positively with age and CMV positivity. The frequency of these cells decreased transiently following transplantation but rebounded to pretransplant levels for up to 1 year following transplantation. CD57+PD1 CD4 T cells proliferate in vitro upon CD3 stimulation when cocultured with unsorted PBMCs in a contact-independent manner. Under these conditions, the majority of CD57+PD1 CD4 T cells downregulate CD57 and upregulate PD1. The latter was further enhanced by rapamycin treatment but inhibited by tacrolimus. These findings indicate that CD57+PD1 CD4 T cells proliferate independently of CoB treatment, but rapamycin may induce exhaustion in CoB resistant T cells to enhance transplant tolerance.

Follicular dendritic cells (FDCs) can retain Ag for long periods of time, a feature that is thought to sustain germinal center (GC) reactions and drive memory B cell responses. Immune complexes (ICs) bind to complement receptors on the FDC surface, subsequently cycling between intracellular compartments and the cell surface before their degradation. In this Top Read, Arulraj et al. (p. 1436) used mathematical modeling to better understand how periodic cycling of ICs in FDCs influences the GC reaction. They used experimental data of sequentially stained PE-ICs on murine FDCs, estimating an average residence time of ICs on the cell surface to be 21 min compared with 36 min within cells. Simulations indicated that redistribution of ICs on the FDC surface via IC cycling can enhance the GC reaction. When including Ag degradation, there is a tradeoff between IC protection within FDCs and availability of IC on the surface of FDC to GC B cells, but blockade of IC cycling can shut down the GC reaction. These findings suggest that IC cycling is a critical mechanism for modulating humoral immune responses in the GC.

Previous work has shown that the more mature, CD16+ macrophages could secrete IL-12 in response to Toxoplasma gondii, whereas the more abundant CD16 monocytes could not. In this Top Read, Muglia Amancio et al. (p. 1642) demonstrates that IFN-γ pretreatment can prime CD16 monocytes to produce IL-12 in response to microbial stimulation. Following incubation with IFN-γ, CD16 but not CD16+ monocytes increased IL-12 secretion when stimulated. The IFN-inducible transcriptional signature of the CD16 monocytes was similar to that of CD16+ monocytes without IFN-γ treatment. IFN-α impaired IFN-γ–induced IL-12 by CD16 monocytes, whereas mTOR pathway inhibition increased IL-12 production by these cells following microbial stimulation. These data suggest that CD16+ monocytes are preconditioned to produce IL-12 and are therefore refractory to effects of both IFN-γ and mTOR inhibition; however, CD16 monocytes require these regulatory signals for optimal IL-12 production.

Memory B cells (MBCs) differentiate into plasma cells (PCs) in response to Ag challenge with greater speed and magnitude compared with naive B cells (nBs), but the molecular mechanisms that contribute to this enhanced response are not completely understood. In this Top Read, Price et al. (p. 1493) characterized the transcriptional and chromatin accessibility profiles of IgM- and IgG-specific MBCs compared with nBs in a mouse model of influenza infection. They observed accessible chromatin in MBC surrounding PC-specific genes, and MBCs had a unique transcriptional profile for genes related to heme metabolism, the cell cycle, and chemotaxis. Heme metabolism was critical to enhanced oxidative phosphorylation and MBC differentiation into PCs. Human and mouse MBCs share similar epigenetic signatures and, together, these results define conserved transcriptional and epigenetic signatures of MBCs with a critical role for heme metabolism.

Although PI3K signaling is critical to plasma cell (PC) differentiation, little is known about transcriptional regulation of PI3K expression in this context. In this Top Read, Xie et al. (p. 1515) analyzed differential expression in PCs versus germinal center B cells compared with naive and memory B cells. The authors confirmed previous studies showing a role for Klf2 in B cell differentiation and observed dramatic downregulation of zinc finger protein Zbtb18 during terminal differentiation to PCs. Zbtb18 functions as a transcriptional corepressor and binds directly to enhancer/promoter regions of PI3K subunit genes, reducing their expression, thus limiting PC differentiation. Zbtb18 is downregulated during the early phases of B cell activation, which resulted in increased PI3K signaling and enhanced PC differentiation in both humans and mice. Somatic mutations in Zbtb18 have been observed in several human cancers, and B cells transduced with different mutated forms of Zbtb18 were unable to regulate PI3K signaling or suppress PC differentiation. These results define a key role for Zbtb18 in regulating PI3K signaling during PC differentiation.