Biology subjects

Sekaly, R.-P.

Publications and source records attributed to Sekaly, R.-P..

15 recordsLinked to original sources

bioRxiv2026

Clinical and Cross-Domain Validation of an LLM-Guided, Literature-Based Gene Prioritization Framework

BackgroundWe previously published a literature-based pipeline for sepsis gene prioritization (PS3 and candidate genes) using an LLM-enabled retrieval and judging framework. Here, we extend that work to ask whether these prioritized genes show independent clinical validity and whether the same strategy generalizes to a drug-obesity- infection setting. MethodsUsing the original LLM-guided workflow, we evaluated PS3 and the Candidate set in two new settings. First, we tested 28-day mortality prediction in the independent VANISH sepsis trial, benchmarking PS3 and Candidate against two established immune signatures--the Severe-or-Mild (SoM) signature and Immune Health Metric (IHM)--under a uniform logistic-regression framework with clinical covariates. Second, we applied the same genome-wide screening and tiered judging pipeline to GLP-1/obesity/infection biology centered on semaglutide, comparing Tier-1 and Tier-2 gene sets to STEP trial serum proteomics at gene and Hallmark pathway levels. In parallel, we fine-tuned an open-weight GPT-OSS-20B model on curated sepsis justifications to obtain a domain-aware "LLM-as-judge," and compared its scoring behavior with the base model on semaglutide Tier-2 genes. ResultsIn the full VANISH cohort, PS3 and the Candidate set showed moderate discrimination, whereas SoM remained the strongest single predictor of 28-day mortality. In the Critical/High APACHE II subgroup, PS3 achieved ROC and precision-recall performance comparable to, or slightly better than, SoM despite its smaller, knowledge-derived composition, indicating that literature-prioritized genes capture mortality-relevant immune dysregulation under severe illness. In the semaglutide case study, gene-level overlap between LLM-prioritized genes and differentially abundant serum proteins was modest, but Tier-1 genes recapitulated the main semaglutide-responsive metabolic programs from STEP and highlighted additional immune-metabolic pathways relevant to infection, with discordances largely explained by serum proteome coverage. The fine-tuned judge remained moderately concordant with the base GPT-OSS across mechanistic themes, preserving overall ranking while inducing systematic, biologically interpretable shifts in immune and infection-related scores. ConclusionsAn LLM-guided, literature-based gene prioritization framework yields compact gene sets that show independent sepsis mortality signal and pathway-level concordance in a semaglutide/obesity/infection setting, while a sepsis-aware LLM-as-judge provides domain-specific refinements without overturning core rankings. Together, these findings support knowledge-grounded, LLM-derived gene sets and judges as interpretable components for probing immune dysregulation across diseases and therapies. Short abstractWe previously published a literature-based pipeline for sepsis gene prioritization (Priority Set 3, PS3, and a Candidate set) using an LLM-enabled retrieval and judging framework; here, we test whether these prioritized genes show independent clinical validity and whether the same strategy generalizes to a drug-obesity-infection setting. Using the original workflow, we first evaluated 28-day mortality prediction in the independent VANISH sepsis trial, benchmarking PS3 and the Candidate set against two established immune signatures--the Severe-or-Mild (SoM) signature and Immune Health Metric (IHM)--within a uniform logistic-regression framework adjusted for clinical covariates. In the full cohort, PS3 and Candidate showed moderate discrimination, while SoM remained the strongest single predictor; however, in the Critical/High APACHE II subgroup, PS3 achieved ROC and precision-recall performance comparable to, or slightly better than, SoM despite its smaller, knowledge-driven composition, indicating that literature-prioritized genes capture mortality-relevant immune dysregulation under severe illness. We then applied the same genome-wide screening and tiered judging pipeline to GLP-1/obesity/infection biology centered on semaglutide, comparing Tier-1 and Tier-2 genes with STEP trial serum proteomics; although gene-level overlap with differentially abundant proteins was modest, Tier-1 genes recapitulated key semaglutide-responsive metabolic programs and highlighted additional immune-metabolic pathways relevant to infection, with discordances largely attributable to serum proteome coverage. Finally, supervised fine-tuning of an open-weight GPT-OSS model on curated sepsis justifications yielded a domain-aware "LLM-as-judge" that remained broadly concordant with the base model while inducing systematic, interpretable shifts in immune and infection-related scores. Together, these results support LLM-guided, literature-based gene sets and judges as compact, mechanistically interpretable components for probing immune dysregulation across diseases and therapies.

bioinformatics↗

bioRxiv2025

Identification of a multi-omics factor predictive of long COVID in the IMPACC study

Following SARS-CoV-2 infection, [~]10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor". IMPACC participants who experienced LC had lower recovery factor scores compared to participants without LC. Biologic characterization revealed increased levels of plasma proteins associated with inflammation, elevated transcriptional signatures of heme metabolism, and decreased androgenic steroids in LC patients. The recovery factor was also associated with altered circulating immune cell frequencies. Notably, recovery factor scores were predictive of LC occurrence in patients as early as hospital admission, irrespective of acute disease severity. Thus, the recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

systems biology↗

bioRxiv2024

Single cell analysis reveals an antiviral network that controls Zika virus infection in human dendritic cells

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10x Genomics Chromium single cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human moDCs infected with ZIKV at the single cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN dependent and independent genes (antiviral module). We modeled the ZIKV specific antiviral state at the protein level leveraging experimentally derived protein-interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for evaluating the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per cell basis with experimental protein interaction data. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool to gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.

microbiology↗

bioRxiv2022

Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses

Systems biology approaches have been used to define molecular signatures and mechanisms of immunity to vaccination. However, most such studies have been done with single vaccines, and comparative analysis of the response to different vaccines is lacking. We integrated temporal transcriptional data of over 3,000 samples, obtained from 820 healthy adults across 28 studies of 13 different vaccines and analyzed vaccination-induced signatures associated with the antibody response. Most vaccines induced similar kinetics of shared transcriptional signatures, including signatures of innate immunity occurring 1-3 days post-vaccination, as well as the canonical plasmablast and cell cycle signatures appearing 7 days post-vaccination. However, the yellow fever vaccine YF-17D uniquely induced an early transient signature of T and B cell activation at Day 1, followed by delayed antiviral/interferon and plasmablast signatures that peaked at Days 7 and 14-21, respectively. Thus, despite the shared transcriptional response to most vaccines, at any given time point there was no evidence for a "universal signature" that could be used to predict the antibody response to all vaccines. However, accounting for the asynchronous nature of responses led to the identification of a time-adjusted signature that improved prediction antibody of responses across vaccines. These results provide a transcriptional atlas of the human immune response to vaccination and define a common, time-adjusted signature of antibody responses to vaccination.

immunology↗

bioRxiv2022

Type I IFN promotes pathogenic inflammatory monocyte maturation during H5N1 infection

Ly6Chi inflammatory monocytes show high IFN responses, and contribute to both protective and pathogenic functions following influenza virus infection. In order to understand the significance of IFN responses in this subset, we examined monocytes during infection with a lethal H5N1 virus that induces high levels of IFN and a low-pathogenicity H1N1 virus that induces low levels of IFN. We show that H5N1 infection results in early recruitment of high numbers of Ly6Chi monocytes and induction of chemokines and Ifnb1. Using unbiased transcriptomic and proteomic approaches, we also find that monocytes are significantly enriched during H5N1 infection and are associated with chemokine and IFN signatures in mice, and with severity of symptoms after influenza virus infection in humans. Recruited Ly6Chi monocytes subsequently become infected in the lung, produce IFN-{beta}, and mature into FasL+ monocyte-derived cells (FasL+MCs) expressing dendritic cell markers. Both Ccr2-/- and Faslgld mice are protected from lethal infection, indicating that monocytes contribute to pathogenesis. Global loss of type I and type III IFN signaling in Stat2-/- mice results in loss of monocyte recruitment, likely reflecting a requirement for IFN-dependent chemokine induction. Here we show that IFN is not directly required for monocyte recruitment on an IFN-sufficient background, but is required for maturation to FasL+MCs. Loss of IFN signaling skews to a Ly6Clo phenotype associated with tissue repair, suggesting that IFN signaling in monocytes is a critical determinant of influenza virus pathogenesis.

immunology↗

bioRxiv2021

The Immune Signatures Data Resource: A compendium of systems vaccinology datasets

Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository1,2. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effects across studies, and the absence of multiple relevant studies from non-HIPC groups in ImmPort. To support comparative analyses across different vaccines, we have created the Immune Signatures Data Resource, a compendium of standardized systems vaccinology datasets. This data resource is available through ImmuneSpace, along with code to reproduce the processing and batch normalization starting from the underlying study data in ImmPort and the Gene Expression Omnibus (GEO). The current release comprises 1405 participants from 53 cohorts profiling the response to 24 different vaccines and includes transcriptional profiles and antibody response measurements. This novel systems vaccinology data release represents a valuable resource for comparative and meta-analyses that will accelerate our understanding of mechanisms underlying vaccine responses. [Table 1]

systems biology↗

bioRxiv2021

HIV-specific CD8 T cells from elite controllers have an epigenetic imprint that preserves effector functions

Several lines of evidence support a central role for CD8 T cells as key determinants in the control of HIV, particularly in rare "elite controllers" who control the virus to undetectable levels in the blood in the absence of antiretroviral therapy (ART). While HIV-specific CD8 T cells isolated from elite controllers have enhanced antiviral cytokine production and proliferative capacity in response to antigen stimulation when compared to cells isolated from viremic or even aviremic ART-suppressed non-controllers, the cell-intrinsic mechanisms underlying the enhanced T cell memory-like function of HIV-specific CD8 T cells in elite controllers remain largely undefined. To identify the transcriptional and epigenetic pathways that regulate functional capacity in HIV-specific CD8 T cells in elite controllers, we performed genome-wide transcriptional and DNA methylation analysis of MHC Class I multimer+ CD8 T cells sorted from aviremic elite controllers compared to aviremic non-controllers on suppressive ART. Co-omics analysis revealed enrichment for gene signatures that support a multipotent differentiation state, cell survival, and a long-lived effector cell fate in HIV-specific CD8 T cells from elite controllers. Specifically, we observed DNA methylation programs at the transcription factor binding sites of the stem-associated factors TCF-1 and LEF1 that delineate HIV-specific CD8 T cells from elite controllers versus ART-treated individuals. HIV-specific CD8 T cells in elite controllers also maintain T cell receptor and IL-12/STAT4 pathway signaling and have suppressed pro-apoptotic TNF pathway signaling. These findings show that HIV-specific CD8 T cells from elite controllers have enhanced expression and DNA methylation programs that maintain developmental potential and in turn promote long-term survival, proliferative potential, and effector capacity. These data also provide new insights into the relationship between stem-associated transcription factors and stable epigenetic restriction of T cell developmental capacity.

immunology↗

bioRxiv2021

An innate immune activation state prior to vaccination predicts responsiveness to multiple vaccines

Many factors determine whether an individual responding to vaccination will generate an immune response that can lead to protection. Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccines. However, the generalizability and mechanisms that underlie this association remain poorly defined. Here, we sought to identify a common pre-vaccination signature and mechanisms that could predict the immune response across a wide variety of vaccines. We leveraged the "Immune Signatures Data Resource" created by the NIH Human Immunology Project Consortium (HIPC) to integrate data from 28 studies involving 13 different vaccines and associate the blood transcriptional status of 820 healthy young adults with their responses. An unsupervised analysis of blood transcriptional profiles across studies revealed three distinct pre-vaccination states, characterized by the differential expression of genes associated with a pro-inflammatory response, cell proliferation, and metabolism alterations downstream of NF{kappa}B and IRF7. Innate and adaptive immune cell subset-specific genes were also associated with the three pre-vaccination states. Importantly, individuals whose pre-vaccination state was enriched in pro-inflammatory response genes known to be downstream of NF{kappa}B tended to have higher serum antibody responses one month after vaccination. A supervised analysis of the same data resulted in a single classifier, also enriched for NF{kappa}B regulated genes, that predicted the antibody response across most of the vaccines. Projection into single-cell RNA-sequencing data suggested that this pre-vaccination state was attributable to the signature of activation of non-classical monocytes and myeloid dendritic cells. Transcriptional signatures of acute responses to bacterial and not viral infections were enriched in the high pro-inflammatory pre-vaccination state and also included NF{kappa}B regulated genes. The pro-inflammatory pre-vaccination state was highly reminiscent of the innate activation state triggered by TLR ligands or adjuvants. These results demonstrate that wide variations in the transcriptional state of the immune system in humans can be a key determinant of responsiveness to vaccination. They also define a transcriptional signature NF{kappa}B activation at baseline, that is associated with a greater magnitude of antibody response to multiple vaccines, and suggest that modulation of the innate immune system by next-generation adjuvants targeting NF{kappa}B before vaccine administration may improve vaccine responsiveness.

systems biology↗

bioRxiv2021

Pre-vaccination Frequency of Circulatory Tfh is associated with Robust Immune Response to TV003 Dengue Vaccine

It has been estimated that more than 390 million people are infected with Dengue virus every year; around 96 millions of these infections result in clinical pathologies. To date, there is only one licensed viral vector-based Dengue virus vaccine CYD-TDV approved for use in dengue endemic areas. While initially approved for administration independent of serostatus, the current guidance only recommends the use of this vaccine for seropositive individuals. Therefore, there is a critical need for investigating the influence of Dengue virus serostatus and immunological mechanisms that influence vaccine outcome. Here, we provide comprehensive evaluation of sero-status and host immune factors that correlate with robust immune responses to a Dengue virus vector based tetravalent vaccine (TV003) in a Phase II clinical cohort of human participants. We observed that sero-positive individuals demonstrate a much stronger immune response to the TV003 vaccine. Our multi-layered immune profiling revealed that sero-positive subjects have increased baseline/pre-vaccination frequencies of circulating T follicular helper (cTfh) cells and the Tfh related chemokine CXCL13/BLC. Importantly, this baseline/pre-vaccination cTfh profile correlated with the vaccinees ability to launch neutralizing antibody response against all four sero-types of Dengue virus, an important endpoint for Dengue vaccine clinical trials. Overall, we provide novel insights into the favorable cTfh related immune status that persists in Dengue virus sero-positive individuals that correlate with their ability to mount robust vaccine specific immune responses. Such detailed interrogation of cTfh cell biology in the context of clinical vaccinology will help uncover mechanisms and targets for favorable immuno-modulatory agents. Author summaryDengue virus (DENV) is a worldwide threat that causes significant health and economic burden. Currently, there are several challenges in the development of a DENV vaccine including the existence of four different serotypes all; capable of causing disease and antibody dependent enhancement (ADE). For complete protection, a vaccine must be able to generate neutralizing antibodies against all 4 serotypes to avoid ADE. Currently, there is one licensed DENV vaccine, CYD-TDV (DENGVAXIATM). However, this vaccine is only efficacious in protecting against severe disease in DENV seropositive individuals therefore serostatus effect must be further studied for optimal vaccine design. A subset of CD4+ T cells called T-follicular helper (Tfh) cells have been well known to play a major role in aiding high affinity antibody production. Therefore, we chose to look at subsets of Tfh and the cytokines they produce in human blood that can serve as biomarkers for effective vaccine design. We found that DENV sero-positive participants had increased pre-vaccination frequencies of Tfh cells and higher levels of the Tfh related chemokine CXCL13/BLC that plays a role in directing antigen-specific responses. This pre-vaccination Tfh profile and CXCL13/BLC are then correlated positively with the vaccinees ability to produce neutralizing antibody against all four sero-types (breadth of the Response) of DENV, an important goal for all DENV vaccine trials.

immunology↗

bioRxiv2021

Infusion of CCR5 Gene-Edited T Cells Allows Immune Reconstitution, HIV Reservoir Decay, and Long-Term Virological Control

Antiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4+ T cells (SB-728-T) led to sustained increases in CD4+ T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and long-term persistence of a novel CCR5 gene-edited CD4+ T memory stem cell (CD45RAintROint TSCM) subset that can replenish the pool of more differentiated memory cells. We showed that novel CD45RAintROint TSCM cells are transcriptionally distinct from the previously described CD45RA+ TSCM and are minimally differentiated cells uncommitted to a specific Th-lineage. Subsequently, we showed in an independent trial that infusion of the SB-728-T cell product resulted in partial control of viral replication upon cessation of ART which was correlated with the frequencies of CCR5 gene-edited TSCM and their TEM progeny. Interestingly, one participant that remained off ART to this date demonstrated long-term maintenance of CCR5 gene-edited cells and increased frequency of polyfunctional HIV-specific CD4+ and CD8+ T cells, contributing to low levels of viral load 5 years post-infusion. Consequently, the generation of HIV protected memory CD4+ T cells by CCR5 disruption can contribute toward novel interventions aimed at achieving a sustained ART-free viral remission of HIV disease.

immunology↗

bioRxiv2021

IL-10 driven memory T cell survival and Tfh differentiation promote HIV persistence

Mechanisms regulating HIV persistence are complex and not well understood. Increased IL-10 levels were positively associated with HIV reservoir in blood and lymph nodes (LN) of treated HIV aviremic individuals. In LNs, B cells, regulatory T cells, follicular T helper cells (Tfh), monocytes and macrophages contributed to the frequencies of IL10+ cells. Cells with HIV DNA in LNs were in close proximity to IL-10+ cells and/or had the active form of STAT3, the transcription downstream of IL-10. Gene signatures and proteins associated to cell survival, Co-inhibitory receptors expression, maintenance of memory T cells, immune metabolism and Tfh frequencies were all modulated by IL-10 and associated with HIV reservoir persistence. In vitro, STAT3 knockout or neutralization of IL-10, reverted all the aforementioned pathways and resulted in 10-fold decay in HIV reservoir. Collectively, these results provide strong evidence for a pivotal role of IL-10 in HIV persistence, and a potential therapeutic strategy for HIV cure.

immunology↗

bioRxiv2021

Sustained IL-15 response signature predicts RhCMV/SIV vaccine efficacy

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work suggests that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including non-canonical T cell receptor (TCR), toll-lie receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly predicting protection. The IL-15 gene expression signature was further evaluated in an independent RM IL-15 treatment cohort, revealing that in whole blood the response to IL-15 is inclusive of innate and adaptive immune gene expression networks that link with RhCMV/SIV vaccine efficacy. We also show that this IL-15 response signature similarly tracks with vaccine protection in an independent RhCMV/SIV vaccination/SIV challenge RM validation cohort. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that enable vaccine-elicited CD8+ T cells to mediate protection against highly pathogenic SIV challenge. Author SummarySIV insert-expressing vaccine vectors based on strain 68-1 RhCMV elicit robust, highly effector-memory-biased T cell responses that are associated with an unprecedented level of SIV control after challenge (replication arrest leading to clearance) in slightly over half of vaccinated monkeys. Since efficacy is not predicted by standard measures of immunogenicity, we used functional genomics analysis of RhCMV/SIV vaccinated monkeys with known challenge outcomes to identify immune correlates of protection. We found that arrest of viral replication after challenge significantly correlates with a vaccine-induced response to IL-15 that includes modulation of T cell, inflammation, TLR signaling, and cell death programming. These data suggest that RhCMV/SIV efficacy is not based on chance, but rather, results from a coordinated and sustained vaccine-mediated induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ effector-memory T cell function, that enable vaccine-elicited CD8+ T cells to mediate efficacy.

genomics↗

bioRxiv2020

Microbiome and Metabolome driven differentiation of TGF-β producing Tregs leads to Senescence and HIV latency

Current therapeutic interventions to eradicate latent HIV ("reservoir") and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, "INRs") and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence driving transcription factors (TFs) FOXO3, SMAD2 and IRF3. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-{beta} signaling cascade are complimented by the downregulation of cell cycle, metabolic and pro-inflammatory pathways. Lactobacillaceae family and metabolites (members of the butyrate family - i.e. -ketobutyrate) were correlated with Treg frequencies in "Senescent-INRs" ex vivo, triggered the differentiation of TGF-{beta} producing Tregs and promoted HIV latency establishment in vitro. These cascades, downstream of PD-1/TGF-{beta}, prevent memory T cell differentiation and are associated with an increase in frequencies of cells with inducible HIV ex vivo. Our findings identify cellular senescence responses that can be targeted by PD-1 or TGF-{beta} specific interventions that have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.

immunology↗

bioRxiv2020

Human follicular CD4 T cell function is defined by specific molecular, positional and TCR dynamic signatures.

The orchestrated interaction between follicular helper CD4 T cells (TFH) and germinal center (GC) B cells is crucial for optimal humoral immunity. However, the regulatory mechanisms behind spatial distribution and function of TFH is not well understood. Here, we studied human TFH cells and found that transitioning to a CD57hi TFH status was associated with distinct positioning in the GC, phenotype, transcriptional signatures, function and downregulation of their T-cell receptor (TCR). Single cell TCR clonotype analysis indicated a unidirectional transition towards the CD57hi TFH status, which was marked with drastic changes in the nature of immunological synapse formation where peripheral microclusters become dominant. Lack of central supra molecular activation cluster (cSMAC) formation in TFH synapse was associated with enhanced ubiquitination/proteasome activity in these cells. Our data reveal significant aspects of the tissue organization and heterogeneity of follicular adaptive immunity and suggest that CD57hi TFH cells are endowed with distinctive programming and spatial positioning for optimal GC B cell help. One Sentence Summaryhuman TFH cell heterogeneity

immunology↗

bioRxiv2020

TCF-1 regulates the stem-like memory potential of HIV-specific CD8+ T cells in elite controllers

Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and non-human primates naturally controlling HIV/SIV infection express more of the transcription factor, TCF-1, than non-controllers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and proliferative capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 controls the stem-like memory properties of HIV-specific CD8+ T cells and provides a rationale for enhancing this pathway in T cell-based therapeutic strategies for HIV. One Sentence SummaryTCF-1 is highly expressed in HIV-specific CD8+ T cells from elite controllers and directly regulates human CD8+ T cell expansion capacity in response to T cell receptor stimulation.

immunology↗