Biology subjects

Anderson, H. D.

Publications and source records attributed to Anderson, H. D..

4 recordsLinked to original sources

bioRxiv2026

Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity

Intestinal V{gamma}4 {gamma}{delta} intraepithelial lymphocytes (IELs) persistently bind the constitutively expressed epithelial ligand BTNL3/8 through germline-encoded T cell receptor (TCR) determinants. While they resemble innate-like T cells such as NKT cells, unlike these populations, V{gamma}4 IELs encounter ligand only after thymic development. Moreover, unlike conventional {beta} T cells, V{gamma}4 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how V{gamma}4 IELs address this challenge. While germline-encoded TCR regions broadly mediate BTNL3 recognition, productive activation requires additional non-germline TCR features that license responsiveness to BTNL3/8 and enable local selection in the gut. Rather than driving exhaustion, BTNL3/8 reactivity directly promotes expression of an NK-like program marked by adaptor molecules that license innate-like signaling in healthy tissue. These findings reveal how combined innate and adaptive features of the {gamma}{delta}TCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.

immunology↗

bioRxiv2024

Epigenetic control of commensal induced Th2 Responses and Intestinal immunopathology

Understanding the initiation of T-helper (Th)-2 immunity is crucial for addressing allergic diseases that have been linked to the commensal microbiota. However, Th2 responses are notably absent from known host-microbiota intestinal immune circuits. Notably, the commensal protist Tritrichomonas induces a transient innate ILC2 circuit rather than a chronic Th2 circuit. Canonical Th2 responses rely on the induction of IL-4 production by innate cells. This study shows that the absence of Tet2, a DNA demethylase, reprograms naive T cells to autonomously produce IL-4 upon T cell receptor stimulation, bypassing the need for IL-4 from innate cells for Th2 differentiation. Loss of this checkpoint induces chronic Th2 responses to Tritrichomonas, associated with IL-25-dependent barrier dysfunction and increased susceptibility to allergic pathology in response to dietary antigens. Sentence SummaryRegulation of cell autonomous IL-4 in T cells is critical to prevent dysregulated Th2 immunity to commensals and predisposition to allergy.

immunology↗

bioRxiv2024

Omega-3 polyunsaturated fatty acids modify glucose metabolism in THP-1 monocytes

Chronic inflammation is a driving factor in diseases like obesity and type 2 diabetes. Enhanced glucose metabolism, including via oxidative phosphorylation, may contribute to heightened immune activation. A recent clinical trial showed that supplementation with the n-3 fatty acid -linolenic acid (ALA) reduced oxidative phosphorylation rates in human monocytes. However, the mechanism remains unknown. Therefore, our objective was to explore the direct effects of ALA and docosahexaenoic acid (DHA) on glucose metabolism in a cell culture model and to explore the molecular mechanism. THP-1 monocytes were treated for 48h with 10-40 M of ALA or DHA and compared with vehicle and oleic acid controls. The Seahorse XFe24 system was used to approximate catabolic rates in the presence of glucose, including glycolysis and oxidative phosphorylation. The latter was validated by respirometry using an Oroboros O2k Oxygraph. Both ALA and DHA treatments reduced oxidative phosphorylation and increased glycolytic rates relative to control conditions. We identified pyruvate dehydrogenase kinase 4 (PDK4), an enzyme that inhibits the conversion of pyruvate to acetyl-CoA, as a possible mechanistic candidate. This gene was significantly upregulated by ALA and, to a greater extent, by DHA. Using fluorescent indicators, we also found that DHA increased reactive oxygen species while ALA had no effect. Our data suggest that ALA and DHA trigger a re-wiring of bioenergetic pathways in monocytes, possibly via the upregulation of PKD4. Given the close relationship between cell metabolism and immune cell activation, this may represent a novel mechanism by which n-3 fatty acids modulate immune function and inflammation.

cell biology↗

bioRxiv2020

Walking Drosophila navigate complex plumes using stochastic decisions biased by the timing of odor encounters

Insects find food, mates, and egg-laying sites by tracking odor plumes swept by complex wind patterns. Previous studies have shown that moths and flies localize plumes by surging upwind at odor onset and turning cross- or downwind at odor offset. Less clear is how, once within the expanding cone of the odor plume, insects use their brief encounters with individual odor packets, whose location and timing are random, to progress towards the source. Experiments and theory have suggested that the timing of odor encounters might assist navigation, but connecting behaviors to individual encounters has been challenging. Here, we imaged complex odor plumes simultaneous with freely-walking flies, allowing us to quantify how behavior is shaped by individual odor encounters. Combining measurements, dynamical models, and statistical inference, we found that within the plume cone, individual encounters did not trigger reflexive surging, casting, or counterturning. Instead, flies turned stochastically with stereotyped saccades, whose direction was biased upwind by the timing of prior odor encounters, while the magnitude and rate of saccades remained constant. Odor encounters did not strongly affect walking speed. Instead, flies used encounter timing to modulate the rate of transitions between walks and stops. When stopped, flies initiated walks using information from multiple odor encounters, suggesting that integrating evidence without losing position was part of the strategy. These results indicate that once within the complex odor plume, where odor location and timing are unpredictable, animals navigate with biased random walks shaped by the entire sequence of encounters.

neuroscience↗