Biology subjects

Tull, T. J.

Publications and source records attributed to Tull, T. J..

3 recordsLinked to original sources

bioRxiv2023

Unanticipated interacting features of human gut-associated lymphoid tissues link microbiota, intestinal immunity and autoimmunity

Gut-associated lymphoid tissue (GALT) is organised lymphoid tissue that is chronically activated by the intestinal microbiota. It generates the IgA response that is critical for intestinal homeostasis. By iterative application of multiplexed technologies, we identify enrichment of double-negative 2 (DN2:CD27-IgD-CD21loCD11chi) B cells in GALT, where they comprise the majority of intraepithelial and subepithelial B cells. We show that DN2 B cells in GALT interact with DC in the sub-epithelial dome that express DNASE1L3 and microbicides. Unlike in mice, DNASE1L3 in humans does not associate with apoptotic debris, but is located between sampled bacteria and host tissue where it is co-expressed with C1Q, consistent with management of bacterial debris. Thus we demonstrate that DN2 B cells that are otherwise associated with lupus nephritis, and DNASE1L3 and C1q that are lupus autoantigens, are microbiota-associated, interacting components of normal intestinal immunity.

immunology↗

bioRxiv2021

Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood

B cells generate antibodies that are essential for immune protection. Major events driving B cell responses occur in lymphoid tissues, which guide antigen acquisition and support cellular interactions, yet complexities of B cell subsets in human lymphoid tissues are poorly understood. Here we perform undirected, global profiling of B cells in matched human lymphoid tissues from deceased transplant organ donors and tracked dissemination of B cell clones. In addition to identifying unanticipated features of tissue-based B cell differentiation, we resolve two clonally independent subsets of marginal zone B cells that differ in cell surface and transcriptomic profiles, tendency to disseminate, distribution bias within splenic marginal zone microenvironment and immunoglobulin repertoire diversity and hypermutation frequency. Each subset is represented in spleen, gut-associated lymphoid tissue, mesenteric lymph node, and also blood. Thus, we provide clarity and diffuse controversy surrounding human MZB - the elephant in the room of human B cell biology.

immunology↗

bioRxiv2020

Human marginal zone B cell development from early T2 progenitors

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2 and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of 4{beta}7 integrin and lower expression of IL4 receptor (IL4R) compared to the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZB). Lineage progression from T1 cells to MZB via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut homing T2 cells is observed in severe SLE and is associated with reduction of MZB and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence and importance for maintaining health.

cell biology↗