Substitution of Glutamic Acid at Position 71 of DRβ1*04:01 Induces Collagen-Specific Tolerance Without Inducing Alloreactivity.

Objective: The DRB1 locus is strongly associated with both susceptibility and resistance to rheumatoid arthritis (RA). DRB1 alleles encoding the VKA or VRA epitope in positions 11, 71 and 74 confer the highest risk of developing RA, while the allele encoding VEA is protective. We therefore investigated the feasibility of creating antigen-specific tolerance without inducing alloreactivity by replacing lysine with glutamic acid at position 71 in DRβ1*04:01.

Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival following Haploidentical Transplant.

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT.

HLA homozygosity is associated with Non-Hodgkin lymphoma.

The "heterozygote advantage" hypothesis has been postulated regarding the role of human leukocyte antigen (HLA) in non-Hodgkin lymphoma (NHL), where homozygous loci are associated with an increased risk of disease. In this retrospective study, we analyzed the HLA homozygosity of 3789 patients with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) at HLA-A, B, C, DRB1 and DQB1 loci compared to 169,964 normal controls. HLA homozygosity at one or more loci was only associated with an increased risk in NHL patients (OR = 1.

Lineage-Specific Relapse Prediction After Haploidentical Transplantation With Post-Transplant Cyclophosphamide Based on Recipient HLA-B-Leader Genotype and HLA-C-Group KIR Ligand.

The role of NK cell alloreactivity on outcomes after T cell-replete haploidentical donor transplantation (HIDT) remains uncertain. After transplantation, newly formed NK cells are licensed through interactions of donor inhibitory KIR (iKIR) and NKG2A receptors with their cognate ligands on recipient cells. Donor NKG2A recognizes HLA-E bound by recipient HLA class I leader peptides, a process requiring methionine (M) at position -21 of the leader sequence.

Arthritogenic peptide binding to DRB1*01 alleles correlates with susceptibility to rheumatoid arthritis.

Genetic susceptibility to rheumatoid arthritis (RA) is often defined by the presence of a shared epitope (QKRAA, QRRAA, or RRRAA) at positions 70-74 in HLA-DRβ1. However, DRβ1*01:01 and 01:02 contain the same QRRAA epitope, but differ considerably in their susceptibility to RA. The purpose of this study was to determine if this difference could be explained by their ability to bind three arthritogenic peptides that we have previously shown to bind to the archetypal RA-susceptible allele, DRβ1*04:01, but not to the resistant DRβ1*08:01 allele.

A Molecular Analysis of the Shared Epitope Hypothesis: Binding of Arthritogenic Peptides to DRB1*04 Alleles.

Objective: The shared epitope hypothesis posits that amino acids QR/KRAA in positions 70-74 of the DRΒ1 chain are responsible for rheumatoid arthritis susceptibility. However, even DRB1*04 alleles containing the shared epitope vary greatly with respect to degrees of susceptibility. This study was undertaken to conduct a molecular examination of the shared epitope hypothesis by measuring binding of arthritogenic peptides to susceptibility and resistance alleles.

Multiple HLA epitopes contribute to type 1 diabetes susceptibility.

Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed.

A canonical Vγ4Vδ4+ γδ T cell population with distinct stimulation requirements which promotes the Th17 response.

We previously reported a subset of γδ T cells in mice which preferentially responds following intradermal immunization with collagen in complete Freund's adjuvant (CFA). These cells express a nearly invariant "canonical" Vγ4Vδ4+ TCR. They are potent producers of IL-17A and promote the development of collagen-induced arthritis.

γδ T cells protect against lung fibrosis via IL-22.

Inflammation-induced pulmonary fibrosis (PF) leads to irreversible loss of lung function and is a predictor of mortality in numerous lung diseases. Why some subjects with lung inflammation but not others develop PF is unclear. In a mouse model of hypersensitivity pneumonitis that progresses to lung fibrosis upon repeated exposure to the ubiquitous microorganism Bacillus subtilis, γδ T cells expand in the lung and inhibit collagen deposition.

Gammadelta T cells and Th17 cytokines in hypersensitivity pneumonitis and lung fibrosis.

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease caused by the repeated inhalation of aerosolized antigens. With chronic exposure to an inhaled antigen, patients are at risk of developing irreversible pulmonary fibrosis as well as an increased morbidity and mortality. Although alphabeta T cells have been shown to be important in the pathogenesis of HP, gammadelta T cells also accumulate in the bronchoalveolar lavage of patients with HP.

The influence of IgE-enhancing and IgE-suppressive gammadelta T cells changes with exposure to inhaled ovalbumin.

It has been reported that the IgE response to allergens is influenced by gammadelta T cells. Intrigued by a study showing that airway challenge of mice with OVA induces in the spleen the development of gammadelta T cells that suppress the primary IgE response to i.p.

IL-17A-expressing T cells are essential for bacterial clearance in a murine model of hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. We previously reported that C57BL/6 mice repeatedly exposed to the ubiquitous microorganism Bacillus subtilis develop mononuclear infiltrates in the lung that contain Vgamma6/Vdelta1(+) gammadelta T cells. In the absence of this T cell subset, mice treated with B.

IL-17-producing gammadelta T cells.

IL-17 is produced not only by CD4(+) alphabeta T cells, but also CD8(+) alphabeta T cells, NKT cells, and gammadelta T cells, plus some non-T cells, including macrophages and neutrophils. The ability of IL-17 to deploy neutrophils to sites of inflammation imparts this cytokine with a key role in diseases of several types. Surprisingly, gammadelta T cells are responsible for much of the IL-17 produced in several disease models, particularly early on.

Allergic airway hyperresponsiveness-enhancing gammadelta T cells develop in normal untreated mice and fail to produce IL-4/13, unlike Th2 and NKT cells.

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory gammadelta T cells. The AHR-enhancing cells belong to the Vgamma1(+) gammadelta T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR.

Gammadelta T lymphocyte homeostasis is negatively regulated by beta2-microglobulin.

Successful application of gammadelta T cells in adoptive cell therapies depends upon our ability to maintain these cells in vivo. Using an adoptive transfer model to study lymphopenia-induced homeostatic expansion, we show that CD8(+) and NK1.1(+) gammadelta T cell subsets are differentially regulated.

Protective role of gammadelta T cells in spontaneous ocular inflammation.

Purpose: A role for gammadelta T cells in immunoregulation has been shown in a number of studies, but in the absence of infection or induced disease, mice lacking gammadelta T cells generally appear to be healthy. That certain mice lacking gammadelta T cells often spontaneously develop keratitis, characterized by a progressive and destructive inflammation of the cornea is reported here.

Methods: The keratitis developing in these mice was characterized in terms of prevalence in males versus females, age of onset, and histologic features.

Role of γδ T Cells in Lung Inflammation.

The resident population of γδ T cells in the normal lung is small but during lung inflammation, γδ T cells can increase dramatically. Histological analysis reveals diverse interactions between γδ T cells and other pulmonary leukocytes. Studies in animal models show that γδ T cells play a role in allergic lung inflammation where they can protect normal lung function, that they also are capable of resolving infection-induced pulmonary inflammation, and that they can help preventing pulmonary fibrosis.

Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis.

Hypersensitivity pneumonitis is an environmental lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. Using a well-established murine model of hypersensitivity pneumonitis, we repeatedly exposed C57BL/6 mice to Saccharopolyspora rectivirgula to investigate whether T cells are required for lung fibrosis. In the absence of alphabeta T cells, TCRbeta(-/-) mice exposed to S.

Dissection of genetic mechanisms governing the expression of serum retroviral gp70 implicated in murine lupus nephritis.

The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is secreted by hepatocytes as an acute phase protein, and it has been thought to be a product of an endogenous xenotropic virus, NZB-X1. However, since endogenous polytropic (PT) and modified polytropic (mPT) viruses encode gp70s that are closely related to xenotropic gp70, these viruses can be additional sources of serum gp70. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of xenotropic, PT, or mPT gp70 RNAs in livers and the genomic composition of corresponding proviruses in various strains of mice, including two different Sgp (serum gp70 production) congenic mice.

Evidence that CD8+ dendritic cells enable the development of gammadelta T cells that modulate airway hyperresponsiveness.

Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by gammadelta T cells. In mice sensitized and challenged with OVA, AHR depends on allergen-specific alphabeta T cells; but Vgamma1+ gammadelta T cells spontaneously enhance AHR, whereas Vgamma4+ gammadelta T cells, after being induced by airway challenge, suppress AHR. The activity of these gammadelta T cell modulators is allergen nonspecific, and how they develop is unclear.

Macrophages express multiple ligands for gammadelta TCRs.

As only a handful of ligands have been identified, the general nature of the ligands recognized by gammadelta T cells remains unresolved. In this study, soluble multimerized gammadelta T cell receptors (smTCRs) representing the TCRs of two gammadelta T cell subsets common in the mouse were used to detect and track their own ligands. Ligands for both subsets were found on resident peritoneal macrophages taken from untreated mice, and the expression of both was further induced by Listeria monocytogenes infection.

gammadelta T cells: an important source of IL-17.

IL-17 is a cytokine that plays an important role in orchestrating innate immune function. In addition, IL-17 has been shown to exacerbate autoimmune diseases. CD4(+) alphabeta T cells, gammadelta T cells, and NK cells all produce IL-17.

Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells.

Murine gammadelta T cell subsets, defined by their Vgamma chain usage, have been shown in various disease models to have distinct functional roles. In this study, we examined the responses of the two main peripheral gammadelta T cell subsets, Vgamma1(+) and Vgamma4(+) cells, during collagen-induced arthritis (CIA), a mouse model that shares many hallmarks with human rheumatoid arthritis. We found that whereas both subsets increased in number, only the Vgamma4(+) cells became activated.

Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells.

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred gammadelta T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vgamma1+Vdelta5+ gammadelta T cells enhanced AHR.