Multifaceted B-cell response to transient HIV viraemia in elite controllers

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

ABSTRACT Chronic HIV infection drives B-cell dysfunction associated with the accumulation of tissue-like memory (TLMs) and activated B cells (MBCs) but decline in resting cells. TLMs express multiple inhibitory receptors lack response to soluble antigens. However, their origin mechanisms driving expansion remain unclear. By using bulk BCR sequencing cell subsets from elite controllers an ART-controlled cohort, we revealed that (CD21 - CD27 cells) were significantly less mutated also diverse than other MBCs, suggesting enrichment for innate-like or they belong a mature subset. Subsequent detailed multi-omics study immune controller transient viraemia demonstrated functional increase Env-reactive IgG MBCs non-TLM phenotype. Single-cell RNA/BCR PMBCs enriched orchestrated TNF-alpha followed by interferon alpha gamma across all subsets. We noted emergence extrafollicular PLD4+ plasmablasts previously undepreciated heterogeneity stable TLM population. identified two distinct subsets: TLM1 (T-bet low ) TLM2 hi differed differentiation stage, isotype use mutational burden. Surprisingly, both (TLM1 more TLM2) IGHV4-34 segment (associated self-reactivity) displayed persistent activation signalling signature, indicating (with indices) strong presence pseudotime analyses contained not only conventional lineages, further highlighting complexity whole compartment. This provides new insight into multifaceted as likely happens during early phase anti-retroviral therapy cessation, contribution which might have important clinical implications anti-HIV vaccine design.

Language: Английский

MLL1 directs gut-associated antibody responses to helminth and bacterial infections

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 22, 2024

Soil-transmitted helminths are one of the most common infections across world, yet how to promote an effective humoral response is not well understood. To ensure response, molecular programs underpin specialization antibody effector subtype microenvironmental signals. Here, we identify methyltransferase mixed-lineage leukemia 1 (MLL1) as a key target IgA-driven responses. Mll1 was increased in germinal center (GC) B cells gut-associated lymphoid tissues, and absence MLL1 mature led significant reductions GCs, IgG1 IgE helminth Trichuris muris. Yet, worm expulsion occurred more rapidly Mll1f/fCd23cre/+ mice compared control first two weeks infection. Accelerated clearance correlated with significantly elevated IgA+ plasma (PC), serum IgA fecal mice. Stimulation vitro confirmed that Mll1-deficiency accelerated formation PC this effect cell-intrinsic. CCR9 identified MLL1-regulated molecule by RNA-sequencing flow cytometry. Correspondingly, infected either T. muris or bacterium C. rodentium IgA+CCR9+ localized large intestine. This tailoring cell IgA-secreting healthier microbiome mice, Thus, study reveals tailor responses infections, which may aid development mucosal vaccines new targeted treatments.

Language: Английский