Scientists analyzing human and mouse pancreatic lymph nodes (PLNs) and spleens have identified a distinct subset of CD4 memory helper T cells associated with type 1 diabetes (T1D). Reported by researchers at the University of Pennsylvania Perelman School of Medicine and the HPAP Consortium, the study findings revealed that a specific subset of CD4 T cells was present in pancreatic lymph nodes from organ donors with active disease, and showed signs of extensive transcriptional and chromatin remodeling, when compared with cells from healthy donors.
These cells, the researchers reported, exhibited high expression of NFKB1 and BACH2 and associated chromatin remodeling. The team’s findings were subsequently corroborated in a T1D mouse model. The collective results may represent a detailed resource for future research that could inform new biomarkers and targeted therapeutics for T1D.
First author Maryam Abedi, PhD, senior author Golnaz Vahedi, PhD, and colleageus, described their findings in Science Immunology, in a paper titled “Joint Profiling of Gene Expression and Chromatin Accessibility in Pancreatic Lymph Nodes and Spleens of Human Type 1 Diabetes,” in which the team stated, “Together, our work defines a conserved transcriptional and epigenetic program of CD4⁺ memory T cells associated with T1D across species.”
During T1D, autoreactive T cells destroy insulin-producing cells in the pancreatic islets. Insulin is a hormone secreted by pancreatic islet beta cells that enables glucose uptake by peripheral tissues. “For over a century, insulin replacement has been the only therapy for individuals with T1D,” the authors wrote.
The mechanisms that drive this autoimmune disease are not well understood, however. “We reasoned that molecular profiling of immune cells in pancreas-proximal immune organs could reveal the identity of immune subsets during disease progression,” the authors continued. To do this, Abedi and colleagues examined PLNs and spleens from a cohort of organ donors that included 13 patients clinically diagnosed with T1D, eight people with islet-targeting autoantibodies (AAb+) but no diabetes diagnosis, and 14 healthy controls. “We performed deep immune profiling on cells residing in the PLN, a critical site for the drainage of immune cells into the pancreas and priming of autoreactive T cells and the spleen tissues,” they explained.
Using single-nucleus multiome profiling, the team could measure chromatin accessibility and gene expression in the same cell, profiling more than one million cells from the organ donors. Their analyses detected significant changes in central memory CD4 T cells and memory B cells. These cells were present in PLNs from both T1D and AAb+ organ donors—the latter of whom showed signs of active disease despite their lack of a diagnosis.
In particular, the cells expressed elevated levels of genes that encode the transcription factors NF-κB and BACH2, accompanied by large alterations in chromatin accessibility of their associated binding sites. The researchers also found that B cells in the spleens of AAb+ and T1D donors exhibited increased interferon-γ and NF-κB signatures. “B cells in the spleens of most AAb+ and T1D donors differ markedly from those of healthy donors, showing elevated interferon-γ and NF-kb signatures,” they wrote.
Turning to a nonobese diabetic (NOD) mouse model of T1D, the authors also found evidence of similar CD4 T cells with upregulated Nfkb1 and Bach2 and epigenetic modifications at presymptomatic stages of disease. “We also show an Nfkb1highBach2high CD4 T cell subset in the PLNs of NOD mice at presymptomatic stages with extensive gene expression and epigenetic similarities to the human CD4 T cell subset,” they wrote. “A better understanding of these NFKB1-BACH2–expressing CD4 T cells may lead to new therapeutic avenues for preventing or delaying T1D onset,” they noted.
To investigate whether the active T1D signatures identified in the T cells and B cells from organ donors could be detected in the circulation, the team turned to existing public data. They found that “genes highly expressed in T1D-specific B and T cell clusters of the spleens could be detected in peripheral blood of T1D donors based on publicly available data collected by independent groups.” Their study, they commented, “… suggests the importance of understanding the molecular features of immune cells in the spleen, as they can inform the development of blood-based biomarkers.”
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