De Luna, N. | Search bioRxiv

bioRxiv2022

Human T follicular helper clones seed the germinal center-resident regulatory pool

How FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe/vaccine recognition and away from self-reactivity remains unsettled. To explore human Tfr cell provenance, function and location heterogeneity, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar Tfr cells clonally related to natural Tregs (nTfr) from those likely induced from Tfh cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were utilized to pinpoint their in situ locations via multi-plex microscopy and establish divergent functional roles. In-silico and tonsil organoid tracking models corroborated the existence of separate Treg-to-nTfr and Tfh-to-iTfr developmental trajectories. In total, we have identified human iTfr cells as a distinct CD38-expressing, GC-resident, Tfh-descended subset that gains suppressive function while retaining capacities for B-cell help whereas CD38- nTfr cells are elite suppressors primarily localized to follicular mantles. Interventions differentially targeting Tfr subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases. One sentence summaryHuman tonsillar Tfr clones descend from either Treg or Tfh lineages and provenance predicts their TCR repertoires, locations and functional characteristics.

immunology↗

bioRxiv2022

Historical contingency drives compensatory evolution and rare reversal of phage resistance

Bacteria and lytic viruses (phages) engage in highly dynamic coevolutionary interactions over time, yet we have little idea of how transient selection by phages might shape the future evolutionary trajectories of their host populations. To explore this question, we generated genetically diverse phage-resistant mutants of the bacterium Pseudomonas syringae. We subjected the panel of mutants to prolonged experimental evolution in the absence of phages. Some populations re-evolved phage sensitivity, while others acquired compensatory mutations that reduced the costs of resistance without altering resistance levels. To ask whether these outcomes were driven by the initial genetic mechanisms of resistance, we next evolved independent replicates of each mutant lineage in the absence of phages. We found a strong signature of historical contingency: some mutations were highly reversible across replicate populations, while others were highly entrenched. Through whole-genome sequencing of bacteria over time, we also found that populations with resistance mutations in the same gene acquired more parallel sets of mutations than populations with resistance mutations in different genes, suggesting that compensatory adaptation is also contingent on how resistance initially evolved. Our study identifies an evolutionary ratchet in bacteria-phage coevolution, and may explain previous observations that resistance persists over time in some bacterial populations but is lost in others. We add to a growing body of work describing the key role of phages in the ecological and evolutionary dynamics of their host communities. Beyond this specific trait, our study provides new insight into the genetic architecture of historical contingency, a crucial component of interpreting and predicting evolution.

evolutionary biology↗