Lack of functional TCR-epitope interaction is associated with herpes zoster through reduced downstream T cell activation.

The role of T cell receptor (TCR) diversity in infectious disease susceptibility is not well understood. We use a systems immunology approach on three cohorts of herpes zoster (HZ) patients and controls to investigate whether TCR diversity against varicella-zoster virus (VZV) influences the risk of HZ. We show that CD4 T cell TCR diversity against VZV glycoprotein E (gE) and immediate early 63 protein (IE63) after 1-week culture is more restricted in HZ patients.

Pre-Existing Immunity to a Nucleic Acid Contaminant-Derived Antigen Mediates Transaminitis and Resultant Diminished Transgene Expression in a Mouse Model of Hepatic Recombinant Adeno-Associated Virus-Mediated Gene Transfer.

Liver injury with concomitant loss of therapeutic transgene expression can be a clinical sequela of systemic administration of recombinant adeno-associated virus (rAAV) when used for gene therapy, and a significant barrier to treatment efficacy. Despite this, it has been difficult to replicate this phenotype in preclinical models, thereby limiting the field's ability to systematically investigate underlying biological mechanisms and develop interventions. Prior animal models have focused on capsid and transgene-related immunogenicity, but the impact of concurrently present nontransgene or vector antigens on therapeutic efficacy, such as those derived from contaminating nucleic acids within rAAV preps, has yet to be investigated.

Variation in the basal immune state and implications for disease.

Analysis of pre-existing immunity and its effects on acute infection often focus on memory responses associated with a prior infectious exposure. However, memory responses occur in the context of the overall immune state and leukocytes must interact with their microenvironment and other immune cells. Thus, it is important to also consider non-antigen-specific factors which shape the composite basal state and functional capacity of the immune system, termed here as I ('I naught').

Utility of nasal swabs for assessing mucosal immune responses towards SARS-CoV-2.

SARS-CoV-2 has caused millions of infections worldwide since its emergence in 2019. Understanding how infection and vaccination induce mucosal immune responses and how they fluctuate over time is important, especially since they are key in preventing infection and reducing disease severity. We established a novel methodology for assessing SARS-CoV-2 cytokine and antibody responses at the nasal epithelium by using nasopharyngeal swabs collected longitudinally before and after either SARS-CoV-2 infection or vaccination.

Prior SARS-CoV-2 Infection Enhances Initial mRNA Vaccine Response with a Lower Impact on Long-Term Immunity.

Spike-encoding mRNA vaccines in early 2021 effectively reduced SARS-CoV-2-associated morbidity and mortality. New booster regimens were introduced due to successive waves of distinct viral variants. Therefore, people now have a diverse immune memory resulting from multiple SARS-CoV-2 Ag exposures, from infection to following vaccination.

Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology.

Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza.

Utility of nasal swabs for assessing mucosal immune responses towards SARS-CoV-2.

Unlabelled: SARS-CoV-2 has caused millions of infections worldwide since its emergence in 2019. Understanding how infection and vaccination induce mucosal immune responses and how they fluctuate over time is important, especially since they are key in preventing infection and reducing disease severity. We established a novel methodology for assessing SARS-CoV-2 cytokine and antibody responses at the nasal epithelium by using nasopharyngeal swabs collected longitudinally before and after either SARS-CoV-2 infection or vaccination.

Establishing thresholds for cytokine storm and defining their relationship to disease severity in respiratory viral infections.

Previous studies have identified cytokines associated with respiratory virus infection illness outcome. However, few studies have included comprehensive cytokine panels, longitudinal analyses, and/or simultaneous assessment across the severity spectrum. This, coupled with subjective definitions of cytokine storm syndrome (CSS), have contributed to inconsistent findings of cytokine signatures, particularly with COVID severity.

Integrated Drivers of Basal and Acute Immunity in Diverse Human Populations.

Prior studies have identified genetic, infectious, and biological associations with immune competence and disease severity; however, there have been few integrative analyses of these factors and study populations are often limited in demographic diversity. Utilizing samples from 1,705 individuals in 5 countries, we examined putative determinants of immunity, including: single nucleotide polymorphisms, ancestry informative markers, herpesvirus status, age, and sex. In healthy subjects, we found significant differences in cytokine levels, leukocyte phenotypes, and gene expression.

Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities.

Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individual's genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored.

Preventing packaging of translatable P5-associated DNA contaminants in recombinant AAV vector preps.

Recombinant adeno-associated virus (rAAV) vectors are increasingly being used for clinical gene transfer and have shown great potential for the treatment of several monogenic disorders. However, contaminant DNA from producer plasmids can be packaged into rAAV alongside the intended expression cassette-containing vector genome. The consequences of this are unknown.

Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination.

Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-naïve hosts.

TCR meta-clonotypes for biomarker discovery with enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs.

T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes - groups of biochemically similar TCRs - that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals.

Integrating T cell receptor sequences and transcriptional profiles by clonotype neighbor graph analysis (CoNGA).

Links between T cell clonotypes, as defined by T cell receptor (TCR) sequences, and phenotype, as reflected in gene expression (GEX) profiles, surface protein expression and peptide:major histocompatibility complex binding, can reveal functional relationships beyond the features shared by clonally related cells. Here we present clonotype neighbor graph analysis (CoNGA), a graph theoretic approach that identifies correlations between GEX profile and TCR sequence through statistical analysis of GEX and TCR similarity graphs. Using CoNGA, we uncovered associations between TCR sequence and GEX profiles that include a previously undescribed 'natural lymphocyte' population of human circulating CD8 T cells and a set of TCR sequence determinants of differentiation in thymocytes.

TCR meta-clonotypes for biomarker discovery with tcrdist3: identification of public, HLA-restricted SARS-CoV-2 associated TCR features.

As the mechanistic basis of adaptive cellular antigen recognition, T cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages antigen-enriched repertoires to form meta-clonotypes - groups of biochemically similar TCRs - that can be used to robustly identify and quantify functionally similar TCRs in bulk repertoires.

Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm.

We pursued a study of immune responses in coronavirus disease 2019 (COVID-19) and influenza patients. Compared to patients with influenza, patients with COVID-19 exhibited largely equivalent lymphocyte counts, fewer monocytes, and lower surface human leukocyte antigen (HLA)-class II expression on selected monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes predicted severe COVID-19 disease.

Nasal Wash Cytokines during Respiratory Viral Infection in Pediatric Allogeneic Hematopoietic Cell-Transplant Recipients.

Allogeneic hematopoietic cell-transplant (alloHCT) recipients are at increased risk of complications from viral respiratory-tract infections (vRTIs). We measured cytokine concentrations in nasal washes (NWs) from pediatric alloHCT recipients to better understand their local response to vRTI. Forty-one immunologic analytes were measured in 70 NWs, collected during and after vRTI, from 15 alloHCT recipients (median age, 11 yr) with 19 episodes of vRTI.

Targeted Immunosuppression Distinguishes COVID-19 from Influenza in Moderate and Severe Disease.

Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of COVID-19 and influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and protein level.

Altered CD4 T cell immunity in nurses occupationally exposed to viral pathogens.

Pathogen exposure, including but not limited to herpesviruses, moulds the shape of the immune system, both at a basal state and in response to immune challenge. However, little is known about the impact of high exposure to other viruses on baseline immune signatures and how the immune system copes with repetitive exposures to maintain a balanced functionality. Here we investigated baseline immune signatures, including detailed T cell phenotyping, antigen-specific CD4 and CD8 T cell responses and cytokine profile in paediatric (PED) nurses, who have high occupational exposure to viral pathogens including varicella zoster virus (VZV) and respiratory viruses, and in neonatal intensive care unit (NICU) nurses, as a control group with infrequent occupational exposure.

Past Life and Future Effects-How Heterologous Infections Alter Immunity to Influenza Viruses.

Influenza virus frequently mutates due to its error-prone polymerase. This feature contributes to influenza virus's ability to evade pre-existing immunity, leading to annual epidemics and periodic pandemics. T cell memory plays a key protective role in the face of an antigenically distinct influenza virus strain because T cell targets are often derived from conserved internal proteins, whereas humoral immunity targets are often sites of increased mutation rates that are tolerated by the virus.

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness.

Approximately 50% of individuals aged 6-49 years in the United States are infected with cytomegalovirus (CMV), with seroprevalence increasing with age, reaching 85-90% by 75-80 years according to Bate et al. (Clin Infect Dis 50 (11): 1439-1447, 2010) and Pawelec et al. (Curr Opin Immunol 24:507-511, 2012).

Quantifiable predictive features define epitope-specific T cell receptor repertoires.

T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 10 (ref. 1) to as high as 10 (ref.