Lymphocytic variant hypereosinophilic syndrome (LHES) is driven by aberrant Th2‑skewed lymphocyte clones that promote tissue eosinophilia. We performed multimodal single‑cell RNA‑sequencing (scRNA‑seq), cell‑surface protein (ADT) profiling, and paired αβ‑TCR sequencing on peripheral‑blood mononuclear cells (PBMCs) from two clinically characterized LHES patients and one idiopathic HES control. One LHES patient was sequenced at two timepoints, pre-JAK inhibitor treatment and post-JAK inhibitor treatment. Single‑cell regulatory‑network inference (SCENIC), CellChat ligand–receptor modelling, and scRNA variant calling were integrated with flow‑cytometric validation and 5,000× amplicon sequencing. Two clonally expanded CD3‑CD4⁺ central‑/effector‑memory T‑cell clusters were observed exclusively in LHES. These cells showed Th2‑associated regulons (<a href="https://www.ncbi.nlm.nih.gov/datasets/gene/2625/">GATA3</a>, <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/10538/">BATF</a>, <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/4094/">MAF</a>), high expression of <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/1233/">CCR4</a>, <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/1043/">CD52</a>, <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/11251/">PTGDR2</a> and <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/3596/">IL13</a>, and down‑regulation of <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/919/">CD247</a> (CD3ζ), a mechanism experimentally confirmed to abolish surface CD3/TCR. Autocrine IL‑7 signaling, predicted by CellChat, provides an antigen‑independent proliferative cue. Therapeutically actionable targets (<a href="https://www.ncbi.nlm.nih.gov/datasets/gene/1233/">CCR4</a>, <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/1043/">CD52</a>, <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/3567/">IL‑5</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/3574">IL‑7</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/7124">TNF</a>) were prioritized; one refractory patient achieved complete clinical and cytologic remission after mogamulizumab (anti‑CCR4) therapy. Longitudinal sequencing revealed clonal evolution with acquisition of a <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/6774/">STAT3</a> p.G618R mutation under JAK‑inhibition, highlighting a resistance mechanism. Raw scRNA‑seq (5′ cDNA, VDJ, ADT) data, and sample‑level metadata will be distributed through dbGaP. These resources provide the first high‑resolution immune atlas of LHES and a framework for rational, precision immunotherapy in eosinophilic disorders.

Cellular Profiling Identifies Targetable T Cell Phenotypes in Lymphocytic Variant Hypereosinophilic Syndrome