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PubMed2024

Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones.

Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.

Animals↗

PubMed2022

Sex Differences in Human Immunodeficiency Virus Persistence and Reservoir Size During Aging.

BACKGROUND: Sex differences in human immunodeficiency virus (HIV) reservoir dynamics remain underexplored. METHODS: Longitudinal samples from virally suppressed midlife women (n = 59, median age 45 years) and age-matched men (n = 31) were analyzed retrospectively. At each time point, we measured sex hormones (by means of enzyme-linked immunosorbent assay) and cellular HIV DNA and RNA (by means of digital droplet polymerase chain reaction). Number of inducible HIV RNA+ cells, which provides an upper estimate of the replication-competent reservoir, was quantified longitudinally in a different subset of 14 women, across well-defined reproductive stages. Mixed-effects models included normalized reservoir outcomes and sex, time since antiretroviral therapy (ART) initiation, and the sex-by-time interaction as predictors. RESULTS: At ART initiation, women and men had median (interquartile range [IQR]) CD4+ T-cell counts of 204/μL (83-306/μL) versus 238/μL (120-284/μL), respectively; median ages of 45 (42-48) versus 47 (43-51) years; and median follow-up times of 79.2/μL (60.5-121.1/μL) versus 66.2/μL (43.2-80.6/μL) months. We observed a significant decline of total HIV DNA over time in both men and women (P < .01). However, the rates of change differed significantly between the sexes (P < .01), with women having a significantly slower rate of decline than men, more pronounced with age. By contrast, the levels of inducible HIV RNA increased incrementally over time in women during reproductive aging (P < .01). CONCLUSIONS: In contrast to men, in whom the HIV reservoir steadily declines with aging, the HIV reservoir in women is more dynamic. Total HIV DNA (including intact and defective genomes) declines more slowly in women than in men, while the inducible HIV RNA+ reservoir, which is highly enriched in replication-competent virus, increases in women after menopause.

Aging↗

PubMed2025

DNA methylation and multi-omics profiling of T cells uncovers chemotactic pathways and proliferation-linked hypomethylation in narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a loss of orexin-producing cells in the brain and involves autoimmune mechanisms, including the presence of autoreactive T cells. In this study, we performed genome-wide DNA methylation analysis using both CD4+/CD8+ T cells from 42 NT1 patients and 42 controls across discovery and replication cohorts. To identify methylation changes more robustly associated with the disease, we prioritized differentially methylated regions (DMRs) over single-site differentially methylated positions (DMPs). Furthermore, to validate and interpret DMP-level associations, we integrated genome-wide genotype and gene expression data obtained from the same individuals. As a result, the DMR analysis identified 15 reproducible DMRs in CD4+ T cells and 5 in CD8+ T cells, with most DMRs shared between the two cell types. Shared DMRs included regions associated with CCL5 (p = 2.1E-02) and CCR4 (p = 8.3E-03). Integrative analysis with genotype and gene expression data also showed that the DMP related to S100A4, which promotes lymphocyte migration through CCR5 and CXCR3 receptors, was associated with the disease in CD4+ T cells. Pathway analysis of genes identified through both the DMR and integrative analyses indicated enrichment in cell chemotaxis-related pathways, suggesting that aberrant chemokine-mediated cell migration plays a central role in NT1 pathogenesis. Further, NT1-associated methylation changes were predominantly hypomethylation events, significantly enriched in non-promoter, non-CpG island regions (p = 1.74E-102). We further observed that global hypomethylation levels were correlated with hypoSC, a mitotic index estimated from methylation data, highlighting increased T cell proliferation in NT1.

Humans↗

PubMed2026

HIV immunological nonresponders show low SKAP1 concentration and DNA hypermethylation in the SKAP1 promotor region.

OBJECTIVE: The aim of this study was to improve understanding of biological pathways underlying inadequate CD4 + T-cell restoration after initiating antiretroviral treatment as these so called Immunological nonresponders are at increased risk for morbidity and mortality while treatment options are lacking. DESIGN: We compared baseline multiomics data from 88 Immunological nonresponders and 1467 immunological responders that participated in the 2000HIV study, separated into a discovery and validation cohort. METHODS: We measured expression levels of 2367 plasma proteins, comparing the immunological responders and nonresponders. As this highlighted low Src kinase-associated phosphoprotein 1 (SKAP1) levels in Immunological nonresponders, we measured intracellular SKAP1 levels in CD4 + T-cells, investigated DNA methylation and assessed single-nucleotide polymorphisms (SNPs). We also explored whether HIV or CMV infection may influence SKAP1 expression. RESULTS: SKAP1 plasma levels were significantly lower in Immunological nonresponders in both cohorts. SKAP1 plasma concentrations reflected intracellular levels in CD4 + T-cells. DNA methylation analysis showed significant hypermethylation at the SKAP1 promotor region. Three SNPs close to the SKAP1 gene were associated with poor Immunological response. Preliminary data suggest that HIV or CMV may influence SKAP1 levels. CONCLUSION: Our data show decreased SKAP1 concentrations in immunological nonresponders, potentially driven by hypermethylation of the SKAP1 promoter. Downregulation of SKAP1, which is known to play a role in T cell proliferation and migration, may therefore contribute to the poor restoration of CD4 + cell count after ART.

Humans↗

PubMed2026

Immune Cell-Stratified Regulatory Contexts Associated With BMI-Related Multi-System Disease Risk: A Cell-Stratified Mendelian Randomization Study Using Single-Cell eQTL Data.

AIMS: Body mass index (BMI) is associated with multisystem disease risk, but the immune cell-specific regulatory contexts underlying BMI-related genetic associations with disease outcomes remain unclear. METHODS: We applied a cell-stratified Mendelian randomization framework integrating European-ancestry BMI GWAS data, GWAS datasets for 33 disease outcomes across five disease systems, single-cell cis-eQTL data from 28 peripheral blood immune cell types, and dynamic CD4+ T cell eQTL data. SuSiE-based colocalization was used to identify BMI-associated loci sharing causal variants with immune-cell gene expression. These variants were used as cell-stratified instruments for Mendelian randomization. RESULTS: Across 28 immune cell types, 1326 colocalized variants regulating 1426 genes were identified. In primary MR analyses, genetically predicted BMI showed Bonferroni-significant associations with 26 disease outcomes. Cell-stratified analyses identified 87 Bonferroni-significant associations across 17 disease outcomes. Cardiovascular diseases showed the broadest cell-stratified associations, followed by respiratory and metabolic diseases. CD4+ T cell regulatory contexts contributed one of the largest shares of prioritized associations, and BMI-related effects varied across CD4+ T cell activation states. Cross-disease prioritization highlighted recurrent immune feature genes, including TRAF3 and FGFR1. CONCLUSION: These findings prioritize CD4+ T cell regulatory contexts as potential immunogenetic links between BMI and multi-system disease risk, while requiring further validation in diverse populations and mechanistic models.

Humans↗

PubMed2004

Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells.

Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct "central memory" CD62L(+) phenotype.

CD4-Positive T-Lymphocytes↗

PubMed2026

Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC.

PURPOSE: Durvalumab therapy following concurrent chemoradiotherapy (cCRT) improves progression-free survival (PFS) in patients with unresectable locally advanced non-small cell lung cancer. In this prospective observational study, we evaluated the changes in peripheral blood immune cell counts to elucidate the immunologic mechanisms underlying cCRT and durvalumab therapy. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cell (PBMC) samples were collected at four time points: before cCRT, after cCRT, at the start of durvalumab, and 8 weeks after the start of durvalumab, and analyzed by multicolor flow cytometry. RESULTS: Of the 149 enrolled patients, 115 received durvalumab consolidation therapy after cCRT. The median PFS in the overall population was 24.2 months, and the 3-year PFS rate was 38.9%. PBMC analysis showed an increased effector fraction of CD4+ T cells before and after cCRT but no change in CD8+ T cells. Following durvalumab therapy, the effector fraction ratio of CD8+ T cells (CD62Llow CD8+ T cells) increased and positively correlated with increased CD62Llow CD4+ T cells during cCRT. Patients whose proportion of CD62Llow CD4+ T cells exceeded the threshold for cCRT had better PFS than those below the threshold. Patients whose CD62Llow CD8+ T-cell proportion exceeded the threshold after durvalumab therapy showed prolonged PFS compared with those below the threshold. CONCLUSIONS: cCRT promotes an increase in effector CD4+ T cells, and the subsequent increase in CD8+ T cells following durvalumab therapy prolongs PFS. Peripheral blood effector-type CD4+ and CD8+ T cells are potential biomarkers for evaluating the immune status of patients and predicting treatment efficacy.

Humans↗

PubMed2026

Shared CD4+ T cell receptor specificity groups in Crohn's disease and ulcerative colitis.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is marked by chronic intestinal inflammation and dysregulated immunity. Although UC and CD affect different areas of the gastrointestinal tract, both diseases share aberrant CD4+ memory T cell responses, with HLA-DRB1 as a major genetic risk factor. HLA-DRB1 encodes MHC class II molecules that influence the CD4+ T cell receptor (TCR) repertoire, yet how these genotypes shape TCR specificity in IBD remains unclear. Here, we genotyped HLA-DRB1 and profiled 3.13 million TCRβ sequences from circulating memory CD4+ T cells in 33 IBD patients (20 UC, 13 CD) and 14 healthy controls. Using the GLIPH2 algorithm, we distilled 468,441 candidates based on CDR3 amino acid motifs into 440 high-confidence TCR specificity groups significantly enriched among individuals sharing HLA-DRB1 alleles. Notably, 5 specificity groups were IBD-enriched and were shared between UC and CD, suggesting common antigen targets in both diseases. We also observed increased frequencies of clonally expanded cytotoxic GZMB+PRF1+ memory CD4+ T cells and KIR+CD8+ T cells in a subset of risk-allele carriers with IBD. These findings elucidate distinct, HLA-linked TCR specificity groups in IBD and provide mechanistic insights that may advance antigen discovery and personalized medicine.

Humans↗

PubMed2026

Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHCII CAR-T cell-treated mice.

In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium-modified (Be-modified) peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirm that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA-seq of lung-resident CCL4/Be tetramer+ CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a potentially novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.

Animals↗

PubMed2026

Single-cell capture of on-ART SIV transcription reveals TGF-β-mediated metabolic control of viral latency.

We previously demonstrated that blocking TGF-β with galunisertib, a safe, orally available small drug, reactivated latent SIV in vivo by shifting T cells toward a transitional effector phenotype. Here, we investigated the mechanisms underlying this effect using single-cell RNA sequencing, metabolic profiling, and high-dimensional spectral flow cytometry of samples from SIV-infected, antiretroviral therapy-treated (ART-treated) macaques before and after galunisertib. To characterize virus-transcribing, infected cells during ART, we developed a novel, sensitive SIV Transcripts Capture Assay (SCAP) that detected 127 SIV-expressing cells within lymph node single-cell transcriptome libraries. Galunisertib drove broad metabolic reprogramming in CD4+ T cells, with transcriptional upregulation of inflammatory and mitochondrial biosynthesis pathways, confirmed by Seahorse profiling. Metabolomics revealed increased energy metabolites and amino acids and enhanced metabolic flux without proliferation. SIV transcript-positive cells before galunisertib were metabolically quiescent compared with cells without detectable viral transcripts. After galunisertib, virus-expressing cells showed a dramatic metabolic activation, with upregulation of glycolysis, fatty acid metabolism, and TNF-α signaling. High-dimensional flow cytometry demonstrated effects beyond CD4+ T cells, including fewer tissue-resident memory T cells, but more inflammatory macrophages. In conclusion, SCAP represents a specific tool for characterizing rare SIV-infected cells transcribing virus during ART, and it reveals TGF-β as a key mediator of viral latency in vivo through metabolic suppression.

Virus Latency↗

PubMed2026

Th2 skewing in patients with disseminated coccidioidomycosis.

BACKGROUNDDisseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4+ T cells toward a Th2 phenotype can exist in the context of DCM. Here, we studied a large population to determine the frequency of abnormal Th2 skewing of CD4+ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this phenotype.METHODSWe collected PBMCs from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4+ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole-genome sequencing was conducted on 180 individuals who also had cytokine profiling.RESULTSWe found that approximately 25% of patients with DCM had a CD4+ T cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Coculture of T cells with the IL-4R/IL-13R-blocking antibody dupilumab reduced Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12/IFN-γ axis in several Th2-skewed patients, and we validated one such variant in IFNGR1 as hypomorphic.CONCLUSIONPatients with DCM, especially males, should be screened for Th2 skewing of CD4+ T cells. Patients with Th2 skewing should be additionally screened for genetic defects in the IL-12/IFN-γ axis. Our findings give a mechanistic rationale for blockade of IL-4R in Th2-skewed patients with refractory coccidioidomycosis.FUNDINGNational Institute of Allergy and Infectious Diseases/NIH grants R21 AI149654 and U19 AI166059 and University of California Office of the President grant VFR-19-633386.

Humans↗

PubMed2026

CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.

Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.

Humans↗

PubMed2025

A targeted CRISPR screen identifies ETS1 as a regulator of HIV-1 latency.

Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV-1 latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV-1 expression. We further investigated one of the identified factors - the transcription factor ETS1, and found that it is required for maintenance of HIV-1 latency in both latently infected cell lines and in a primary CD4 T cell latency model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV-1 expression in actively infected cells, but increased HIV-1 expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV-1 expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV-1 (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV-1 reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV-1 expression. Furthermore, the impact of ETS1 depletion on HIV-1 expression in latently infected cells was partially dependent on MALAT1. Additionally, we demonstrate that ETS1 knockout resulted in enhanced abundance of activating modifications (H3K9Ac, H3K27Ac, H3K4me3) on histones located at the HIV-1 long terminal repeat (LTR), indicating that ETS1 regulates the activity of chromatin-targeting complexes at the HIV-1 LTR. Overall, these data demonstrate that ETS1 is an important regulator of HIV-1 latency that impacts HIV-1 expression through repressing MALAT1 expression and by regulating modification of proviral histones.

Proto-Oncogene Protein c-ets-1↗