Kirn, A. | bioRxiv Science

bioRxiv2024

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

Soil-transmitted helminths are one of the most common infections globally, yet how to promote effective gut-associated humoral responses is not well understood. We identify the histone methyltransferase MLL1 as a key target to promote IgA-driven responses. Mll1 was increased in germinal center B cells in gut-associated lymphoid tissues, and Mll1-deficiency led to changes in the histone modification H3K4me3 on key B cell and immune-regulatory genes. Correspondingly, MLL1-deficient B cells had defective germinal centers and IgG1 in response to the helminth Trichuris muris. Yet, Mll1f/fCd23cre/+ mice expelled worms more rapidly compared to control mice. Accelerated worm clearance correlated with elevated IgA+ plasma cells, as well as both serum and fecal IgA. RNA-sequencing identified CCR9 as a key MLL1-regulated molecule. As such, Mll1f/fCd23cre/+ mice infected with T. muris had increased IgA+CCR9+ PC localized in the large intestine. Regulation of IgA by MLL1 was confirmed beyond T. muris infection. In vitro cultures confirmed Mll1-deficiency increased IgA+ plasma cells in a B cell-intrinsic manner, and IgA production was also increased in Mll1f/fCd23cre/+ mice infected with the bacterium C. rodentium. This study reveals MLL1 as a key target to promote IgA responses to gut-associated infections.

immunology↗

bioRxiv2024

Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity

Adaptive immune responses protect against multiple classes of pathogens, including viral, bacterial, fungal, and helminth infections. In all these settings, CD4+ T follicular helper (Tfh) cells tailor high-affinity class-switched B cells responses. How Tfh lineage sovereignty is established while allowing for this context-specific functional heterogeneity is unclear. Here, we identify Tfh transcriptional networks in response to diverse infections. While Bcl-6 is the transcriptional linchpin of the core Tfh signature, this is overlayed with pathogen-specific transcriptional modules that shape Tfh function. Cytokine-transcriptional Tfh programing in mouse and human lymphoid tissue demonstrated that type I interferon and TGF{beta} signaling direct individual Tfh subpopulations to instruct B cell output. Here, we provide a transcriptional map and cell surface resource to interrogate Tfh diversity in humans and mice. This resource can be leveraged to further understand the origins of immune flexibility, perform immune monitoring in infection and antibody-mediated diseases and to develop context-specific vaccines. ONE-SENTENCE SUMMARYDalit, Tan and colleagues provide a resource that functionally and transcriptionally profiles T follicular helper cells (Tfh) during diverse pathogen responses to reveal a blueprint for transcriptional flexibility and new tools to interrogate Tfh heterogeneity in mice and humans.

immunology↗