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To date, structural analysis has demonstrated a highly consistent binding pattern of the TCR to the MHC molecule. Rossjohn and colleagues reveal the first structures of two human T reg cell TCRs and show that they bind with a reversed polarity to the MHC. Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT reg ) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT reg TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.

Aims/hypothesisThe aim of this study was to determine if retention of C-peptide following immunotherapy using recombinant GAD65 conjugated to aluminium hydroxide (GAD-alum) is influenced by HLA risk haplotypes DR3-DQ2 and DR4-DQ8.MethodsHLA-dependent treatment effect of GAD-alum therapy on C-peptide retention in individuals with recent-onset type 1 diabetes was evaluated using individual-level patient data from three placebo-controlled, randomised clinical trials using a mixed repeated measures model.ResultsA significant and dose-dependent effect was observed in individuals positive for the genotypes that include HLA-DR3-DQ2 but not HLA-DR4-DQ8 and in the broader subgroup of individuals positive for all genotypes that include HLA-DR3-DQ2 (i.e. including those also positive for HLA-DR4-DQ8). Higher doses (three or four injections) showed a treatment effect ratio of 1.596 (95% CI 1.132, 2.249; adjusted p = 0.0035) and 1.441 (95% CI 1.188, 1.749; adjusted p = 0.0007) vs placebo for the two respective HLA subgroups.Conclusions/interpretationGAD65-specific immunotherapy has a significant effect on C-peptide retention in individuals with recent-onset type 1 diabetes who have the DR3-DQ2 haplotype.

CD4 + T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit 59-71 and α-enolase-15cit 10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β−74cit 69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit 10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6 + and human TRAV26-1 + TCR-HLA-DR4 complexes presenting vimentin-64cit 59-71 and α-enolase-15cit 10-22 , respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes. CD4 + T cells recognising shared susceptibility epitope (SE) encoded HLA-DRB1 presenting citrullinated self-peptides are implicated in rheumatoid arthritis. Here the authors characterise the T cell receptor repertoire and structure during recognition of different citrullinated self-epitopes in HLA-DR4 transgenic mice and ACPA + RA patients.

We describe here a shared surface and cell wall protein, endoglucanase 2 (Eng2), expressed on the etiological agents that cause the endemic systemic mycoses of North America - Blastomyces, Coccidioides, and Histoplasma. We demonstrate that, despite sequence variation of the protein across these related fungi, exposure to Eng2 vaccinated and protected inbred and humanized HLA-DR4 strains of mice against lethal experimental infections with these fungi by eliciting adaptive immunity mediated by CD4+ T cells. We also show that CD4+ T cell precursors against Eng2 were detectable in naive individuals and that patients who had recovered from these infections evinced a memory and recall CD4+ T cell response to Eng2 and its immunodominant epitopes that we have mapped. We created and cataloged new tools and information, such as immunodominant peptide epitopes of Eng2 from each fungus recognized by inbred mice and humans, and we engineered peptide-MHC II tetramers to track T cells in inbred and HLA-DR4-humanized mice. These tools and tetramers will be useful for those who study these infections in mice and humans. Last, because most patients demonstrated immune memory and recall responses against Eng2, our work offers tools for the diagnosis of this collection of infectious diseases across North America.

Our goals were to determine the effect of gender on the clinical features and treatment outcome of type 1 autoimmune hepatitis, and to assess synergisms with the known genetic risk factors. Clinical findings and treatment outcomes were compared in 144 women and 41 men who were also assessed for HLA DR3, HLA DR4, HLA DR3 and DR4 alleles, and the DRB1*1501-DQA1*102 haplotype by polymerase chain reaction. A total of 102 healthy men and women were similarly typed. Women were distinguished from men by higher frequencies of concurrent immune diseases (34% vs 17%, p = 0.05) and HLA DR4 (49% vs 24%, p = 0.007), as had been previously reported. Women, however, had a higher occurrence of non-DRB1*0401 DR4 alleles than men (15% vs 0%, p = 0.02), and men had a lower frequency of these alleles than did normal male subjects (0% vs 16%, p = 0.04). Men and women responded similarly to therapy. Treatment failure occurred more frequently in men only if they had HLA DR3 and women had HLA DR4 (25% vs 4%, p = 0.01). The DRB1*1501-DQA1*102 haplotype did not affect outcome. Gender influences susceptibility and clinical manifestations, but not outcome. Women have HLA DR4 more commonly than men, but this difference relates to their higher frequency of non-DRB1*0401 DR4 alleles. Female gender may promote risk associated with different HLA DR4 alleles.

In this cohort study involving 6403 children at increased risk for celiac disease on the basis of HLA haplotype, the risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 26% and 12%, respectively, in those who were homozygous for the DR3–DQ2 haplotype. Patients with celiac disease or type 1 diabetes often carry at least one copy of HLA haplotype DR3–DQ2.5 cis (DRB1*03-DQA1*05:01-DQB1*02:01) or DR4–DQ8 (DRB1*04-DQA1*03-DQB1*03:02). The DR3–DQ2.5 cis haplotype (characterized by the cis arrangement of DQA1*05:01 and DQB1*02:01 on the same copy of chromosome 6) is present in more than 90% of patients with celiac disease. The remainder of patients with this disease carry either the aforementioned HLA haplotype DR4–DQ8 or the DQ2.5 risk alleles but in trans on the genotype DR7–DQ2.2 (DR7-DQA1*02:01-DQB1*02:02)/DR5–DQ3.5 (DR5-DQA1*05:01-DQB1*03:01). The identification of one of these haplotypes is not, by itself, sufficient for the diagnosis of celiac disease, . . .

Peptides were designed to induce immune tolerance to the major antigen associated with house dust mite (HDM) allergy, Der p 1. HDM is commonly associated with allergic responses in allergic rhinitis and asthma, with Der p 1 specific T-cells implicated in ongoing disease. Tolerogenic peptide immunotherapy can induce tolerance in pathogenic T-cells, bypass mast cell activation and hence reduce the risk of anaphylaxis. A pan-DR binding epitope of Der p 1, covering the broad population, was tested for efficacy in HLA-DR transgenic mice. Potential pan-HLA-DR binding tolerogenic T-cell epitopes from Der p 1 were predicted and manufactured (synthetic peptides A-E). Participants included HDM sensitised (allergic rhinitis/asthma, n=25), non-HDM sensitised (atopic controls sensitised to ≥1 other aero-allergens, n=10) and non-atopic healthy controls, n=10). Peripheral blood mononuclear cells (PBMC) were collected and screened for immune responses to Der p 1 or test peptides A-E. Mapping of minimal T-cell epitopes, apitope (antigen-processing independent epitope) validation and tolerance induction were tested in HLA-DR transgenic mice. HDM-sensitised subjects have an elevated response to pan-DR binding peptide D 30mer. Peptide analogue D121B, containing the minimal epitope and optimised for solubility, was verified as a tolerogenic apitope and induced tolerance against Der p 1 antigens in HLA-DR4 transgenic mice . A tolerogenic peptide, apitope D121B, reduces T-cell immune responses to Der p 1 and is a promising candidate for further development as an immunotherapy for HDM-associated allergic rhinitis and asthma.

CD4+ T cells orchestrate adaptive immune responses via binding of antigens to their receptors through specific peptide/MHC-II complexes. To study these responses, it is essential to identify protein-derived MHC-II peptide ligands that constitute epitopes for T cell recognition. However, generating cells expressing single MHC-II alleles and isolating these proteins for use in peptide elution or binding studies is time consuming. Here, we express human MHC alleles (HLA-DR4 and HLA-DQ6) as native, noncovalent αβ dimers on yeast cells for direct flow cytometry-based screening of peptide ligands from selected antigens. We demonstrate rapid, accurate identification of DQ6 ligands from pre-pro-hypocretin, a narcolepsy-related immunogenic target. We also identify 20 DR4-binding SARS-CoV-2 spike peptides homologous to SARS-CoV-1 epitopes, and one spike peptide overlapping with the reported SARS-CoV-2 epitope recognized by CD4+ T cells from unexposed individuals carrying DR4 subtypes. Our method is optimized for immediate application upon the emergence of novel pathogens.

Prior studies identified HLA class-II and 57 additional loci as contributors to genetic susceptibility for type 1 diabetes (T1D). We hypothesized that race and/or ethnicity would be contextually important for evaluating genetic risk markers previously identified from Caucasian/European cohorts. We determined the capacity for a combined genetic risk score (GRS) to discriminate disease-risk subgroups in a racially and ethnically diverse cohort from the southeastern U.S. including 637 T1D patients, 46 at-risk relatives having two or more T1D-related autoantibodies (≥2AAb + ), 790 first-degree relatives (≤1AAb + ), 68 second-degree relatives (≤1 AAb + ), and 405 controls. GRS was higher among Caucasian T1D and at-risk subjects versus ≤ 1AAb + relatives or controls ( P  < 0.001). GRS receiver operating characteristic AUC (AUROC) for T1D versus controls was 0.86 ( P  < 0.001, specificity = 73.9%, sensitivity = 83.3%) among all Caucasian subjects and 0.90 for Hispanic Caucasians ( P  < 0.001, specificity = 86.5%, sensitivity = 84.4%). Age-at-diagnosis negatively correlated with GRS ( P  < 0.001) and associated with HLA-DR3/DR4 diplotype. Conversely, GRS was less robust (AUROC = 0.75) and did not correlate with age-of-diagnosis for African Americans. Our findings confirm GRS should be further used in Caucasian populations to assign T1D risk for clinical trials designed for biomarker identification and development of personalized treatment strategies. We also highlight the need to develop a GRS model that accommodates racial diversity.

Abstract Context Autoimmune diabetes can develop at any age, but unlike early-onset diabetes, adult onset is less well documented. We aimed to compare, over a wide age range, the most reliable predictive biomarkers for this pathology: pancreatic-autoantibodies and HLA-DRB1 genotype. Methods A retrospective study of 802 patients with diabetes (aged 11 months to 66 years) was conducted. Pancreatic autoantibodies at diagnosis: insulin autoantibodies (IAA), glutamate decarboxylase autoantibodies (GADA), islet tyrosine phosphatase 2 autoantibodies (IA2A), and zinc transporter-8 autoantibodies (ZnT8A) and HLA-DRB1 genotype were analyzed. Results Compared with early-onset patients, adults had a lower frequency of multiple autoantibodies, with GADA being the most common. At early onset, IAA was the most frequent in those younger than 6 years and correlated inversely with age; GADA and ZnT8A correlated directly and IA2A remained stable. The absence of HLA-DRB1 risk genotype was associated with higher age at diabetes onset (27.5 years; interquartile range [IQR], 14.3-35.7), whereas the high-risk HLA-DR3/DR4 was significantly more common at lower age (11.9 years; IQR, 7.1-21.6). ZnT8A was associated with DR4/non-DR3 (odds ratio [OR], 1.91; 95% CI, 1.15-3.17), GADA with DR3/non-DR4 (OR, 2.97; 95% CI, 1.55-5.71), and IA2A with DR4/non-DR3 and DR3/DR4 (OR, 3.89; 95% CI, 2.28-6.64, and OR, 3.08; 95% CI, 1.83-5.18, respectively). No association of IAA with HLA-DRB1 was found. Conclusion Autoimmunity and HLA-DRB1 genotype are age-dependent biomarkers. Adult-onset autoimmune diabetes is associated with lower genetic risk and lower immune response to pancreatic islet cells compared with early-onset diabetes.