Biology subjects

Henrickson, S. E.

Publications and source records attributed to Henrickson, S. E..

6 recordsLinked to original sources

bioRxiv2026

T cell dysregulation and remodeling in pediatric obesity and weight loss

Obesity is a chronic inflammatory disease associated with immune dysregulation. However, alterations in adaptive immune function remain unclear, particularly in the setting of childhood obesity and weight loss. We defined peripheral T cell dysregulation in a cross-sectional cohort of pediatric participants across weight categories and in a longitudinal cohort of adolescents with severe obesity undergoing bariatric surgery. We found increased expression of activation markers (including PD-1 and CD69) in non-naive CD8+ T cells whereas non-naive CD4+ T cells were skewed towards Tfh, Th17, and mixed Th2/Th17 populations. Consistent with a hyperactive state, T cells had enhanced capacity for inflammatory cytokine production (including IFN-{gamma} and TNF-), along with enrichment of gene sets associated with cytokine signaling, cell proliferation, and cell death. Notably, these phenotypic, functional, and transcriptional alterations were not fully resolved after bariatric surgery, despite clinically meaningful weight loss. Together, these findings demonstrate that pediatric obesity leads to dysregulation of adaptive immune function with incomplete normalization after weight loss. SUMMARYThe impact of pediatric obesity on immune cell function is not well understood. This study demonstrates that both CD4+ and CD8+ T cells are dysregulated in children living with obesity and further identifies that this dysregulated state persists following clinically significant weight loss.

immunology↗

bioRxiv2025

Multimodal analysis defines GNG4 as a distinguishing feature of germinal center-positioned CD4 T follicular helper cells in humans

CD4 T follicular helper (Tfh) cells coordinate humoral immune responses within germinal centers (GC) of lymphoid tissue. Despite their critical roles in vaccination and autoimmunity, the gene expression programs that define functionally distinct human Tfh states-- and the molecular pathways engaged by Tfh positioned within the GC niche--remain incompletely understood. This gap has limited translational efforts to monitor or therapeutically target specific Tfh states for clinical benefit. Here, we delineate human CD4 T cell heterogeneity in tonsils and peripheral blood using trimodal single-cell sequencing and spectral flow cytometry to define epigenomic, transcriptional, and proteomic features of distinct Tfh states. Tfh with a GC-like phenotype exhibited markedly increased chromatin accessibility and both mRNA and protein expression of G protein subunit gamma 4 (GNG4). In tonsil, single-cell spatial transcriptomics defined GNG4 expression as a distinguishing feature of activated Tfh states within spatially demarcated GC compartments, with greater specificity than conventionally GC-associated features such as BCL6, TOX2, and S1PR2. In contrast, GNG4- Tfh primarily localized to nonGC regions and exhibited a resting, Th17-polarized phenotype. Together, these data highlight GNG4 as a central feature of activated, GC-positioned Tfh cell identity in humans. One Sentence SummaryGNG4 expression defines activated CD4 T follicular helper cells localized to the germinal center of human lymphoid tissue.

immunology↗

bioRxiv2024

Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome

Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRD). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity. The molecular mechanisms by which STAT3 GOF variants drive this pathology remain unclear. We found that naive CD8+ T cells have an increased capacity for IFN-{gamma} and TNF- secretion. Given this dysregulation of CD8+ T cell function, we evaluated changes in immunoregulatory pathways and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while expression of CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization of cytokine secretion scaled with normalization of CD73 and A2AR. This suggests that a dysregulated purinergic signaling axis plays an important role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other inflammatory disorders with amplified STAT signaling. One Sentence SummaryAmplified STAT3 signaling in CD8+ T cells from STAT3 GOF patients alters purinergic signaling and dysregulates CD8+ T cell function.

immunology↗

bioRxiv2024

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.

immunology↗

bioRxiv2019

Mutation of an L-Type Calcium Channel Gene Leads to a Novel Human Primary Cellular Immunodeficiency

Human primary immunodeficiencies are inherited diseases that can provide valuable insight into the immune system. Calcium (Ca2+) is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and Cav channels. Here we describe three Cav1.4-deficient siblings presenting with X-linked incomplete congenital stationary night blindness as well as an immune phenotype characterized by several recurrent infections. Complete exome sequencing demonstrated that the patients share only a single pathogenic allele; a R625X (p.Arg625Ter) point mutation that leads to a premature stop codon in the CACNA1F gene encoding the L-type Ca2+ channel Cav1.4. The subjects uniformly exhibited an expansion of central and effector memory T lymphocytes, and evidence of T lymphocytes exhaustion with corresponding upregulation of inhibitory receptors. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Finally, the T lymphocytes from patients and CACNA1F knockdown Jurkat T lymphocytes exhibited a reduced Ca2+ flux, compared to controls. This is the first example where the mutation of any Cav channel causes a primary immunodeficiency in humans and establishes the physiological importance of Cav channels in the human immune system.

immunology↗

bioRxiv2019

SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a new T cell checkpoint

SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 KO mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 KO CD8 T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1xSLAMF6 KO cells, and upon activation, they acquired an effector-memory phenotype. Blocking LAG-3 improved the function of SLAMF6 deficient T cells even further. Finally, adoptive transfer of Pmel-1xSLAMF6 KO T cells into melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. These results support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8 T cells to eradicate tumors.

physiology↗