Examining the conditions associated with establishing plasma cell persistence.

Plasma cells (PC) produce antigen-specific antibodies following vaccination or infection, playing a vital role in protective immunity. Not all PC have equal lifespans, yet how lifespans are determined remains unknown. Here, we describe a system for the generation of persistent PC in mice following B cell transfer after in vitro activation.

IL-21 contributes to type 2 memory B cell formation.

Type 2 memory B cells (mBC2), identified in mice as IgG1+CD23+IL-4Rα+CD38+ B cells, which require IL-4 for genesis, are precursors for IgE plasma cells (PC) and considered key in allergy. While IL-21 is critical for normal mBC differentiation, its involvement in mBC2 formation is unknown. Here, we show that although IL-21R-deficient (IL-21R-/-) mice immunized with ovalbumin generated ovalbumin-specific mBC2, their abundances were lower than in controls one-week post-immunization.

Antibody responses against bacterial glycans affinity mature and diversify in germinal centers.

Anti-carbohydrate antibodies (Abs) play crucial roles in pathogen control, but their generation remains poorly understood. By studying responses to in humans, we reveal that the glycan-targeted response shifts from IgM towards IgG and IgA memory with age and antigen exposure across blood, spleen, and tonsils. Both natural colonization and controlled human infection with increased class-switched B cells, with evidence of within-clone switching.

Syndecans and glycosaminoglycans influence B-cell development and activation.

Syndecans (SDCs) are glycosaminoglycan-containing cell surface proteins with diverse functions in the immune system with SDC1 (CD138) and SDC4 expressed in B-lineage cells. Here, we show that stem cells lacking either molecule generate fewer B-cell progenitors but give rise to mature B cells in vivo. Deletion of the plasma cell "marker" CD138 has no effect on homeostatic or antigen-induced plasma cell formation.

IL-21 promotes plasmablast differentiation independently of proliferation in vitro.

Antibodies of the IgE and IgG1 isotypes are relevant for type 2 immunity. In vivo, the production of both is elevated by IL-4, but differentially affected by IL-21, with IgE suppressed and IgG1 production enhanced by IL-21. However, whether the cytokines drive these outcomes primarily by impacting antibody-secreting, proliferating plasmablasts (PB), or their germinal center B cell precursors, is challenging to unravel.

BCR ligation selectively inhibits IgE class switch recombination.

Mechanisms that restrict class switch recombination (CSR) to IgE limit the subsequent production of IgE antibodies and therefore the development of allergic disease. Mice with impaired B cell receptor (BCR) signaling have significantly increased IgE responses, consistent with a role for BCR signaling in IgE regulation. While prior work focused on BCR signaling in IgE-expressing cells to explain these findings, it has been reported that BCR signaling can reduce CSR.

Conversion of vaccines from low to high immunogenicity by antibodies with epitope complementarity.

Existing antibodies (Abs) have varied effects on humoral immunity during subsequent infections. Here, we leveraged in vivo systems that allow precise control of antigen-specific Abs and B cells to examine the impact of Ab dose, affinity, and specificity in directing B cell activation and differentiation. Abs competing with the B cell receptor (BCR) epitope showed affinity-dependent suppression.

Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement.

The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen-receptor gene rearrangements occurred.

Predicting plasma cell retention and loss over a lifetime.

Plasma cells (PCs) rely on external survival cues for persistence, which limits the size of the PC pool. How, then, are new specificities incorporated into a saturated system? In this issue of Immunity, Simons and Karin put forward a mathematical framework to explain PC retention that makes testable predictions about steady-state lifespan structure, withstands tests based on accrual and displaceability, and accounts for lifespan stratification with specificity.

STAT6 tunes maximum T cell IL-4 production from stochastically regulated Il4 alleles.

T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL-4 reporter mice in culture and in vivo following exposure to type 2 immunogens.

The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans.

The existence of long-lived IgE antibody-secreting cells (ASC) is contentious, with the maintenance of sensitization by the continuous differentiation of short-lived IgE ASC a possibility. Here, we review the epidemiological profile of IgE production, and give an overview of recent discoveries made on the mechanisms regulating IgE production from mouse models. Together, these data suggest that for most individuals, in most IgE-associated diseases, IgE ASC are largely short-lived cells.

24 h Hydration profile of collegiate soccer players training once versus twice per day in the heat.

This study examined 24-h hydration parameters among collegiate, male soccer players (n = 17) during twice (X2) and once (X1) per day practice schedules in the heat. Urine specific gravity (USG) and body mass were measured before morning practices, afternoon practice (X2)/team meeting (X1), and the next morning practices. Fluid intake, sweat losses, and urinary losses were assessed during each 24-h window.

Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan.

Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60 days.

B cell receptor ligation induces IgE plasma cell elimination.

The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination.

It takes a sec(22b) to accrue plasma cells.

A recent study shows that the SNARE protein Sec22b plays a key role in antibody-secreting plasma cell accrual. Without Sec22b, antibody titres were diminished, and plasma cells rare to undetectable. The few plasma cells that were detected were functionally compromised, with altered organelle morphology and deficient antibody production.

Long-lived plasma cells accumulate in the bone marrow at a constant rate from early in an immune response.

Vaccines work largely by generating long-lived plasma cells (LLPCs), but knowledge of how such cells are recruited is sparse. Although it is clear that LLPCs preferentially originate in germinal centers (GCs) and relocate to survival niches in bone marrow where they can persist for decades, the issues of the timing of LLPC recruitment and the basis of their retention remain uncertain. Here, using a genetic timestamping system in mice, we show that persistent PCs accrue in bone marrow at an approximately constant rate of one cell per hour over a period spanning several weeks after a single immunization with a model antigen.

Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells.

Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC.

IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation.

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation, and competitiveness in the response, largely through determining access to T cell help. However, how T cell-derived signals contribute to these outcomes is incompletely understood.

The concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21.

Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ.

The benefit of boosters: diversity and inclusion in the COVID-19 memory response.

In a new study, a group evaluate immune responses against SARS-CoV-2 in vaccinated individuals and find evidence of durable immune memory for at least 6 months, irrespective of former infection.

A systemic immune challenge to model hospital-acquired infections independently regulates immune responses after pediatric traumatic brain injury.

Background: Traumatic brain injury (TBI) is a major cause of disability in young children, yet the factors contributing to poor outcomes in this population are not well understood. TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization, and such infections may modify TBI pathobiology and recovery. In this study, we hypothesized that a peripheral immune challenge such as lipopolysaccharide (LPS)-mimicking a hospital-acquired infection-would worsen outcomes after experimental pediatric TBI, by perpetuating the inflammatory immune response.

A Dangerous Liaison with a Conscience.

The contribution of the immunoglobulin E (IgE)-mast cell response to allergy portrays the axis as a villain with malicious intent. A new study from Starkl et al. tells a different story, highlighting a more worthwhile purpose of protecting us against bacterial toxins.

How intrinsic and extrinsic regulators of plasma cell survival might intersect for durable humoral immunity.

Plasma cells (PC) are key to protective immunity because they secrete antibodies. Surviving for periods ranging from days to decades in mammals, PC possess varying survival times that cannot be entirely stochastic or extrinsically set, as presumed half-lives vary with antigenic specificity. Here, we review the signals that impart survival potential to PC.