Biomedical subjects

George A Kuchel

Publications and source records attributed to George A Kuchel.

3 recordsLinked to original sources

PubMed2026

Post-vaccination expansion of extrafollicular Th10 and regulatory Tfr cells distinguishes strong from weak influenza vaccine responses in older adults.

Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-γ responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4+ T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5 + CXCR3 + ICOS + CD38 +) and influenza-specific Th10 (CXCR5 - CXCR3 + PD1 + IL10 +) cells, whereas weak responders expanded regulatory cTfr (CXCR5 + FOXP3 +) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza-specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4+ T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.

Journal Article↗

PubMed2026

p21-senescent cells drive pancreatic islet dysfunction through targetable paracrine signaling in type 2 diabetes.

Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodeling of the cellular secretory profile. In humans, pancreatic β cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β cell senescence to islet dysfunction remains unknown, and thus the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21+ β cells induced secondary senescence in neighboring cells, characterized by dysfunction and loss of identity. JAK inhibitors counteracted the induction of secondary senescence and restored β cell function in islets from humans with T2D and in mice fed a high-fat diet. These findings reveal the critical role of p21+ β cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.

Animals↗

PubMed2026

Dose-dependent IFN programs in myeloid cells after mRNA and adenovirus COVID-19 vaccination.

BACKGROUNDThe SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all 3 FDA-approved COVID-19 vaccines at single-cell multiomic resolution.METHODSWe longitudinally profiled SARS-CoV-2-naive adults (n = 31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multiomic data (DOGMA-Seq).RESULTSWe discovered a distinct, transient IFN program termed ISG-dim, which emerged specifically 1-2 days after the first mRNA dose in approximately 10% of myeloid cells. This state was characterized by ISGF3 complex activation and its target genes (e.g., MX1, MX2, DDX58), with transcriptional and epigenetic profiles distinct from the robust IFN program observed after mRNA boosting or a single Ad26.COV2.S dose (ISG-high). In vitro stimulation of human monocytes showed that IFN-α alone recapitulates ISG-dim, whereas both IFN-α and IFN-γ are required for ISG-high.CONCLUSIONThese findings define dose-dependent IFN programming in human myeloid cells and highlight mechanistic differences between priming and boosting, with implications for optimizing vaccine platform choice, dose scheduling, and formulation.FUNDINGNIH grants AI142086, U19 AI135972, U01 AI165452, U01 AI165452, R01 AI160706, and P30 AG067988.

Humans↗