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. ASC longevity past 60 days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying "long-lived" ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement.

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. Affinity-based selection was evident in persisting PCs, reflecting a relative and dynamic rather than absolute affinity threshold as evidenced by the changing pattern of VH gene somatic mutations conveying increased affinity for antigen. We conclude that the life span of persistent, antigen-specific PCs is in part intrinsic, preprogrammed, and varied and that their final number is related to the duration of the response in a predictable way. This implies that modulating vaccines to extend the duration of the GC reaction will enhance antibody-mediated protective immunity.

The Amount of BCL6 in B Cells Shortly after Antigen Engagement Determines Their Representation in Subsequent Germinal Centers.

It is unknown whether the incremental increases in BCL6 amounts in antigen-activated B cells influence the unfolding differentiation before germinal center (GC) formation. By comparing shortly after immunization the distribution of conventional B cells to those enforced to express BCL6 at the upper quartile of normal and those lacking BCL6 altogether, we determined that B cell representation in the stages before the GC compartment was related to BCL6 amounts. This was not by increased proliferation or suppression of early plasmablast differentiation, but rather by preferential recruitment and progression through these early stages of B cell activation, culminating in preferential transition into GC. Once established, this bias was stable in GC over several weeks; other BCL6-regulated GC B cell behaviors were unaffected. We propose that setting BCL6 amounts very early in activated B cells will be central in determining clonal representation in the GC and thus memory populations.

Paclitaxel inhibits killing by murine cytotoxic T lymphocytes in vivo but not in vitro.

To kill antigen-specific target cells (TCs), cytotoxic T lymphocytes (CTLs) reorganise their microtubule cytoskeleton to deliver lytic granules to the TCs. We used two drugs that stabilise microtubules, paclitaxel and peloruside, to determine how the stabilising microtubule network affects CTL function in vitro and in vivo. In vitro, neither paclitaxel nor peloruside inhibited antigen-specific killing, lytic granule delivery to the cell surface, nor interferon-gamma release by murine CTLs. In contrast, in an in vivo murine model of antigen-induced killing, a single dose of paclitaxel had a significant inhibitory effect on killing by CTLs. Furthermore, the inhibitory effect of paclitaxel was not caused by specific deletion of the effector CTL population in drug-treated mice. The findings reveal that microtubule-stabilising drug treatment can lead to immediate impairment of CTL function without affecting lytic granule release. The results also suggest that patients undergoing taxane anti-cancer therapy may be impaired in their ability to fight infection before the anti-mitotic effects of paclitaxel are apparent.