Corrigendum: Patients with juvenile idiopathic arthritis have decreased clonal diversity in the CD8 T cell repertoire response to influenza vaccination.

[This corrects the article DOI: 10.3389/fimmu.2024.

Patients with juvenile idiopathic arthritis have decreased clonal diversity in the CD8 T cell repertoire response to influenza vaccination.

Recurrent exposures to a pathogenic antigen remodel the CD8 T cell compartment and generate a functional memory repertoire that is polyclonal and complex. At the clonotype level, the response to the conserved influenza antigen, M1 has been well characterized in healthy individuals, but not in patients receiving immunosuppressive therapy or with aberrant immunity, such as those with juvenile idiopathic arthritis (JIA). Here we show that patients with JIA have a reduced number of M1 specific RS/RA clonotypes, indicating decreased clonal richness and, as a result, have lower repertoire diversity.

Role of cross-reactivity in cellular immune targeting of influenza A M1 variant peptide epitopes.

The immunologic significance of cross-reactivity of TCR recognition of peptide:MHC complexes is still poorly understood. We have described TCR cross-reactivity in a system involving polyclonal CD8 T cell recognition of the well characterized influenza viral M1 epitope. While M1 is generally conserved between influenza A isolates, error-prone transcription generates stable variant RNA during infection which could act as novel epitopes.

Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage.

Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell-mediated destruction of pancreatic β cells. We have previously shown that diabetogenic CD8 T cells in the islets of non-obese diabetic mice are phenotypically heterogeneous, but clonal heterogeneity remains relatively unexplored. Here, we use paired single-cell RNA and T-cell receptor sequencing (scRNA-seq and scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of non-obese diabetic mice.

How Drivers of Seasonality in Respiratory Infections May Impact Vaccine Strategy: A Case Study in How Coronavirus Disease 2019 (COVID-19) May Help Us Solve One of Influenza's Biggest Challenges.

Vaccines against seasonal infections like influenza offer a recurring testbed, encompassing challenges in design, implementation, and uptake to combat a both familiar and ever-shifting threat. One of the pervading mysteries of influenza epidemiology is what causes the distinctive seasonal outbreak pattern. Proposed theories each suggest different paths forward in being able to tailor precision vaccines and/or deploy them most effectively.

Single-cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ T-cell lineage that induces GI tract GVHD.

Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft-versus-host disease (GVHD). CD4+ T cells that produce granulocyte-macrophage colony stimulating factor (GM-CSF) have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T-cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if a unique CD4+ GM-CSF+ subset exists that differs from other defined T helper subtypes.

Incorporating calendar effects to predict influenza seasonality in Milwaukee, Wisconsin.

Social outings can trigger influenza transmission, especially in children and elderly. In contrast, school closures are associated with reduced influenza incidence in school-aged children. While influenza surveillance modelling studies typically account for holidays and mass gatherings, age-specific effects of school breaks, sporting events and commonly celebrated observances are not fully explored.

Age-Based Dynamics of a Stable Circulating Cd8 T Cell Repertoire Component.

T-cell memory to pathogens can be envisioned as a receptor-based imprint of the pathogenic environment on the naïve repertoire of clonotypes. Recurrent exposures to a pathogen inform and reinforce memory, leading to a mature state. The complexity and temporal stability of this system in man is only beginning to be adequately described.

IL-27 promotes NK cell effector functions via Maf-Nrf2 pathway during influenza infection.

Influenza virus targets epithelial cells in the upper respiratory tract. Natural Killer (NK) cell-mediated early innate defense responses to influenza infection include the killing of infected epithelial cells and generation of anti-viral cytokines including interferon gamma (IFN-γ). To date, it is unclear how the underlying cytokine milieu during infection regulates NK cell effector functions.

Surveillance Study of Influenza Occurrence and Immunity in a Wisconsin Cohort During the 2009 Pandemic.

Background: Antibody and T-cell immunity to conserved influenza virus antigens can protect animals against infection with diverse influenza strains. Although immunity against conserved antigens occurs in humans, whether such responses provide cross-protection in humans and could be harnessed as the basis for universal influenza vaccines is controversial. The 2009 pandemic provided an opportunity to investigate whether pre-existing cross-reactive immunity affected susceptibility to infection.

Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes.

The T cell repertoire is a function of thymic V(D)J rearrangement and of peripheral selection. The mature repertoire embodies TCR sequences that are important for survival and can identify important structural aspects of the TCR. Analysis of the circulating TCRBV19 CD8 T cell repertoire showed that a majority of NDN-encoded CDR3 amino acid motifs start at CDR3 position four, well within the V region.

CDR3 motif generation and selection in the BV19-utilizing subset of the human CD8 T cell repertoire.

The amino acids at the V-J rearrangement junction of TCR are encoded by the D region and by N or P nucleotides. Together they comprise the NDN region, the specific pMHC selection surface of the TCR β-chain. As an extension of our earlier work on the recall response to influenza M158-66 in HLA-A2 individuals, we have been analyzing the circulating BV19 CD8 T cell repertoires.

CDR3 clonotype and amino acid motif diversity of BV19 expressing circulating human CD8 T cells.

Generating a detailed description of human T cell repertoire diversity is an important goal in the study of human immunology. The circulation is the source of most T cells used for studies in humans. Here we use high throughput sequencing of TCR BV19 transcripts from CD8 T cells derived from unmanipulated PBMC from an older HLA-A2 individual to provide a quantitative and qualitative description of the clonotypic CDR3 nucleotide and amino acid composition of the TCR β-chain from this subset of circulating CD8 T cells.

The functional CD8 T cell memory recall repertoire responding to the influenza A M1(58-66) epitope is polyclonal and shows a complex clonotype distribution.

The CD8 memory T cell repertoire to the influenza A derived M1(58-66) epitope shows a restricted V genes and CDR3 sequences usage. The repertoire is highly polyclonal and the clonotype distribution has been described as consisting of two components, one showing a power law-like distribution and the other composed of a few clonotypes with a very high relative frequency. The question is whether the complex repertoire defined by its ability to flourish in a short term recall culture corresponded to functional cells.

Cross-reactivity of T cells and its role in the immune system.

T-cell receptors recognize peptides presented by the major histocompatibility complex (MHC) on the surface of antigen-presenting cells (APC). The ability of the T-cell receptor (TCR) to recognize more than one peptide-MHC structure defines cross-reactivity. Cross-reactivity is a documented phenomenon of the immune system whose importance is still under investigation.

The TCR repertoires of regulatory and conventional T cells specific for the same foreign antigen are distinct.

The relationship between the TCR repertoires of natural regulatory T cells (nTregs) and conventional CD4(+) T cells (Tconv) capable of responding to the same antigenic epitope is unknown. In this study, we used TCRβ-chain transgenic mice to generate polyclonal nTreg and Tconv populations specific for a foreign Ag. CD4(+) T cells from immunized 3.

Developmental dynamics of post-selection thymic DN iNKT.

Background: Invariant natural killer T (iNKT) cells develop in the thymus and branch off from the maturation pathway of conventional T cell at the DP stage. While different stages of iNKT cellular development have been defined, the actual time that iNKT cell precursors spend at each stage is still unknown.

Methodology/principal Finding: Here we report on maturation dynamics of post-selection DN iNKT cells by injecting wild-type DP(dim) thymocytes into the thymus of TCRα(-/-) mice and using the Vα14-Jα18 rearrangements as a molecular marker to follow the maturation dynamics of these cells.

Cross-reactive responses to modified M1₅₈-₆₆ peptides by CD8⁺ T cells that use noncanonical BV genes can describe unknown repertoires.

Memory T-cell repertoires are populated by clonotypes selected by an individual's history of antigen exposures. Our previous analysis of middle-age CD8(+) T-cell memory repertoires to the influenza-derived epitope M1(58-66) , described a network of highly cross-reactive BV19 clonotypes responding to M1(58-66) and at least one peptide with a conservative amino acid substitution at either of two TCR contact positions. Here, we report that some substitutions abrogate BV19 responses and favor responses with different BV.

A Peptide/MHCII conformer generated in the presence of exchange peptide is substrate for HLA-DM editing.

The mechanism of HLA-DM (DM) activity is still unclear. We have shown that DM-mediated peptide release from HLA-DR (DR) is dependent on the presence of exchange peptide. However, DM also promotes a small amount of peptide release in the absence of exchange peptide.

Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease.

Chronic GVHD is a major cause of morbidity and mortality in allogeneic stem cell transplantation recipients and typically develops from antecedent acute GVHD. In contrast to acute GVHD, chronic GVHD has much broader tissue involvement and clinical manifestations that bear striking similarity to what is observed in autoimmune diseases. How autoimmunity arises out of alloimmunity has been a longstanding unresolved issue.

Enthalpy-entropy compensation and cooperativity as thermodynamic epiphenomena of structural flexibility in ligand-receptor interactions.

Ligand binding is a thermodynamically cooperative process in many biochemical systems characterized by the conformational flexibility of the reactants. However, the contribution of conformational entropy to cooperativity of ligation needs to be elucidated. Here, we perform kinetic and thermodynamic analyses on a panel of cycle-mutated peptides, derived from influenza H3 HA(306-319), interacting with wild type and a mutant HLA-DR.

High-throughput detection method for influenza virus.

Influenza virus is a respiratory pathogen that causes a high degree of morbidity and mortality every year in multiple parts of the world. Therefore, precise diagnosis of the infecting strain and rapid high-throughput screening of vast numbers of clinical samples is paramount to control the spread of pandemic infections. Current clinical diagnoses of influenza infections are based on serologic testing, polymerase chain reaction, direct specimen immunofluorescence and cell culture (1,2).

A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity.

Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity.

The polyclonal CD8 T cell response to influenza M158-66 generates a fully connected network of cross-reactive clonotypes to structurally related peptides: a paradigm for memory repertoire coverage of novel epitopes or escape mutants.

Cross-reactivity of T cells is defined as recognition of two or more peptide-MHC complexes by the same T cell. Although examples of cross-reactivity have been reported, a detailed examination of cross-reactivity has not been performed. In this study, we took advantage of the high degree of polyclonality in the BV19 T cell repertoire responding to influenza M1(58-66) in HLA-A2 individuals to obtain a measure of simple cross-reactivity.

Selective T cell expansion during aging of CD8 memory repertoires to influenza revealed by modeling.

The aging of T cell memory is often considered in terms of senescence, a process viewed as decay and loss of memory T cells. How senescence would affect memory is a function of the initial structure of the memory repertoire and whether the clonotypes that make up the repertoire decay at random. We examine this issue using the T cell memory generated to the conserved influenza A epitope M1(58-66), which induces a strong, focused, but polyclonal CD8 T cell response in HLA-A2 individuals.