ImmunoHorizons最新文献

{"title":"Characterization of the Structural Requirements for the NADase Activity of Bacterial Toll/IL-1R domains in a Course-based Undergraduate Research Experience.","authors":"Tamara Vallejo-Schmidt, Cheyenne Palm, Trinity Obiorah, Abra Rachida Koudjra, Katrina Schmidt, Alexis H Scudder, Eber Guzman-Cruz, Lenora Paige Ingram, Britney C Erickson, Victoria Akingbehin, Terra Riddick, Sarah Hamilton, Tahreem Riaz, Zachary Alexander, Jasmine T Anderson, Charlotte Bader, Phoebe H Calkins, Sumra S Chaudhry, Haley Collins, Maimunah Conteh, Tope A Dada, Jaira David, Daniel Fallah, Raquel De Leon, Rachel Duff, Itohan R Eromosele, Jaliyl K Jones, Nastaran Keshmiri, Mark A Mercanti, Jaine Onwezi-Nwugwo, Michael A Ojo, Emily R Pascoe, Ariana M Poteat, Sarah E Price, Dalton Riedlbauer, Louis T A Rolle, Payton Shoemaker, Alanna Stefano, Michaela K Sterling, Samina Sultana, Lindsey Toneygay, Alexa N Williams, Sheeram Nallar, John E Weldon, Greg A Snyder, Michelle L D Snyder","doi":"10.4049/immunohorizons.2300062","DOIUrl":"10.4049/immunohorizons.2300062","url":null,"abstract":"<p><p>TLRs initiate innate immune signaling pathways via Toll/IL-1R (TIR) domains on their cytoplasmic tails. Various bacterial species also express TIR domain-containing proteins that contribute to bacterial evasion of the innate immune system. Bacterial TIR domains, along with the mammalian sterile α and TIR motif-containing protein 1 and TIRs from plants, also have been found to exhibit NADase activity. Initial X-ray crystallographic studies of the bacterial TIR from Acinetobacter baumannii provided insight into bacterial TIR structure but were unsuccessful in cocrystallization with the NAD+ ligand, leading to further questions about the TIR NAD binding site. In this study, we designed a Course-Based Undergraduate Research Experience (CURE) involving 16-20 students per year to identify amino acids crucial for NADase activity of A. baumannii TIR domain protein and the TIR from Escherichia coli (TIR domain-containing protein C). Students used structural data to identify amino acids that they hypothesized would play a role in TIR NADase activity, and created plasmids to express mutated TIRs through site-directed mutagenesis. Mutant TIRs were expressed, purified, and tested for NADase activity. The results from these studies provide evidence for a conformational change upon NAD binding, as was predicted by recent cryogenic electron microscopy and hydrogen-deuterium exchange mass spectrometry studies. Along with corroborating recent characterization of TIR NADases that could contribute to drug development for diseases associated with dysregulated TIR activity, this work also highlights the value of CURE-based projects for inclusion of a diverse group of students in authentic research experiences.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Turbo, a TLR Ligand-based Adjuvant for Glycoconjugate Vaccines.","authors":"Kishore R Alugupalli","doi":"10.4049/immunohorizons.2400040","DOIUrl":"10.4049/immunohorizons.2400040","url":null,"abstract":"<p><p>Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, which polarizes the response toward the IgG1 isotype, Turbo promoted Ab class switching to all IgG isotypes with affinity maturation; the magnitude of this IgG response is durable and accompanied by the presence of long-lived plasma cells in the mouse bone marrow. In striking contrast with the pathways employed by alum, Turbo adjuvanticity is independent of NLPR3, pyroptotic cell death effector Gasdermin D, and canonical and noncanonical inflammasome activation mediated by Caspase-1 and Caspase-11, respectively. Turbo adjuvanticity is primarily dependent on the MyD88 axis and is lost in mice deficient in costimulatory molecules CD86 and CD40, indicating that Turbo adjuvanticity includes activation of these pathways. Because Turbo formulations containing either monophosphoryl lipid A or TLR2 ligands, Pam2CysSerLys4, and Pam3CysSerLys4 help generate Ab response of all IgG isotypes, as an adjuvant Turbo can improve the immunogenicity of glycoconjugate vaccines against a wide range of bacterial pathogens whose elimination requires appropriate IgG isotypes.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Lymphatic IKKα Disrupts Lung Immune Homeostasis, Drives BALT Formation, and Protects against Influenza.","authors":"Michelle D Cully, Julianne E Nolte, Athena Patel, Andrew E Vaughan, Michael J May","doi":"10.4049/immunohorizons.2400047","DOIUrl":"10.4049/immunohorizons.2400047","url":null,"abstract":"<p><p>IκB kinase (IKK)α controls noncanonical NF-κB signaling required for lymphoid organ development. We showed previously that lymph node formation is ablated in IkkαLyve-1 mice constitutively lacking IKKα in lymphatic endothelial cells (LECs). We now reveal that loss of IKKα in LECs leads to the formation of BALT in the lung. Tertiary lymphoid structures appear only in the lungs of IkkαLyve-1 mice and are not present in any other tissues, and these highly organized BALT structures form after birth and in the absence of inflammation. Additionally, we show that IkkαLyve-1 mice challenged with influenza A virus (IAV) exhibit markedly improved survival and reduced weight loss compared with littermate controls. Importantly, we determine that the improved morbidity and mortality of IkkαLyve-1 mice is independent of viral load and rate of clearance because both mice control and clear IAV infection similarly. Instead, we show that IFN-γ levels are decreased, and infiltration of CD8 T cells and monocytes into IkkαLyve-1 lungs is reduced. We conclude that ablating IKKα in LECs promotes BALT formation and reduces the susceptibility of IkkαLyve-1 mice to IAV infection through a decrease in proinflammatory stimuli.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral T Cell Development and Immunophenotyping of Twins with Heterozygous FOXN1 Mutations.","authors":"Kelsey Voss, Todd Bartkowiak, Allison E Sewell, Channing Chi, Madelyn D Landis, Samuel Schaefer, Heather H Pua, James A Connelly, Jonathan M Irish, Jeffrey C Rathmell, Saara Kaviany","doi":"10.4049/immunohorizons.2400006","DOIUrl":"10.4049/immunohorizons.2400006","url":null,"abstract":"<p><p>The transcription factor FOXN1 plays an established role in thymic epithelial development to mediate selection of maturing thymocytes. Patients with heterozygous loss-of-function FOXN1 variants are associated with T cell lymphopenia at birth and low TCR excision circles that can ultimately recover. Although CD4+ T cell reconstitution in these patients is not completely understood, a lower proportion of naive T cells in adults has suggested a role for homeostatic proliferation. In this study, we present an immunophenotyping study of fraternal twins with low TCR excision circles at birth. Targeted primary immunodeficiency testing revealed a heterozygous variant of uncertain significance in FOXN1 (c.1205del, p.Pro402Leufs*148). We present the immune phenotypes of these two patients, as well as their father who carries the same FOXN1 variant, to demonstrate an evolving immune environment over time. While FOXN1 haploinsufficiency may contribute to thymic defects and T cell lymphopenia, we characterized the transcriptional activity and DNA binding of the heterozygous FOXN1 variant in 293T cells and found the FOXN1 variant to have different effects across several target genes. These data suggest multiple mechanisms for similar FOXN1 variants pathogenicity that may be mutation specific. Increased understanding of how these variants drive transcriptional regulation to impact immune cell populations will guide the potential need for therapeutics, risk for infection or autoimmunity over time, and help inform clinical decisions for other variants that might arise.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Flow Cytometric, Immunohistologic, and Molecular Assessment of Thymus Function in Rhesus Macaques.","authors":"Laura P Hale, Andrew N Macintyre, Dawn E Bowles, Jean Kwun, Jie Li, Barbara Theriot, Joseph W Turek","doi":"10.4049/immunohorizons.2300112","DOIUrl":"10.4049/immunohorizons.2300112","url":null,"abstract":"<p><p>The critical importance of the thymus for generating new naive T cells that protect against novel infections and are tolerant to self-antigens has led to a recent revival of interest in monitoring thymic function in species other than humans and mice. Nonhuman primates such as rhesus macaques (Macaca mulatta) provide particularly useful animal models for translational research in immunology. In this study, we tested the performance of a 15-marker multicolor Ab panel for flow cytometric phenotyping of lymphocyte subsets directly from rhesus whole blood, with validation by thymectomy and T cell depletion. Immunohistochemical and multiplex RNA expression analysis of thymus tissue biopsies and molecular assays on PBMCs were used to further validate thymus function. Results identify Ab panels that can accurately classify rhesus naive T cells (CD3+CD45RA+CD197+ or CD3+CD28+CD95-) and recent thymic emigrants (CD8+CD28+CD95-CD103+CD197+) using just 100 µl of whole blood and commercially available fluorescent Abs. An immunohistochemical panel reactive with pan-cytokeratin (CK), CK14, CD3, Ki-67, CCL21, and TdT provides histologic evidence of thymopoiesis from formalin-fixed, paraffin-embedded thymus tissues. Identification of mRNAs characteristic of both functioning thymic epithelial cells and developing thymocytes and/or molecular detection of products of TCR gene rearrangement provide additional complementary methods to evaluate thymopoiesis, without requiring specific Abs. Combinations of multiparameter flow cytometry, immunohistochemistry, multiplex gene expression, and TCR excision circle assays can comprehensively evaluate thymus function in rhesus macaques while requiring only minimal amounts of peripheral blood or biopsied thymus tissue.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian Control of the Response of Macrophages to Plasmodium Spp.-Infected Red Blood Cells.","authors":"Priscilla Carvalho Cabral, Vincent R Richard, Christoph H Borchers, Martin Olivier, Nicolas Cermakian","doi":"10.4049/immunohorizons.2400021","DOIUrl":"10.4049/immunohorizons.2400021","url":null,"abstract":"<p><p>Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory Profiles Induced by Intranasal Immunization with Ricin Toxin-immune Complexes.","authors":"Lindsey E Tolman, Nicholas J Mantis","doi":"10.4049/immunohorizons.2400007","DOIUrl":"10.4049/immunohorizons.2400007","url":null,"abstract":"<p><p>The underlying contribution of immune complexes in modulating adaptive immunity in mucosal tissues remains poorly understood. In this report, we examined, in mice, the proinflammatory response elicited by intranasal delivery of the biothreat agent ricin toxin (RT) in association with two toxin-neutralizing mAbs, SylH3 and PB10. We previously demonstrated that ricin-immune complexes (RICs) induce the rapid onset of high-titer toxin-neutralizing Abs that persist for months. We now demonstrate that such responses are dependent on CD4+ T cell help, because treatment of mice with an anti-CD4 mAb abrogated the onset of RT-specific Abs following intranasal RICs exposure. To define the inflammatory environment associated with RIC exposure, we collected bronchoalveolar lavage fluid (BALF) and sera from mice 6, 12, and 18 h after they had received RT or RICs by the intranasal route. A 32-plex cytometric bead array revealed an inflammatory profile elicited by RT that was dominated by IL-6 (>1500-fold increase in BALF) and secondarily by KC (CXCL1), G-CSF, GM-CSF, and MCP-1. RICs induced inflammatory profiles in both BALF and serum response that were similar to RT, albeit at markedly reduced levels. These results demonstrate that RICs retain the capacity to induce local and systemic inflammatory cytokines/chemokines that, in turn, may influence Ag sampling and presentation in the lung mucosa and draining lymph nodes. A better understanding of the fate of immune complexes following intranasal delivery has implications for the development of mucosal vaccines for biothreats and emerging infectious diseases.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T Cell Activators Exhibit Distinct Downstream Effects on Chimeric Antigen Receptor T Cell Phenotype and Function.","authors":"Sarah Underwood, Jianjian Jin, Lipei Shao, Michaela Prochazkova, Rongye Shi, Hannah W Song, Ping Jin, Nirali N Shah, Robert P Somerville, David F Stroncek, Steven L Highfill","doi":"10.4049/immunohorizons.2400008","DOIUrl":"10.4049/immunohorizons.2400008","url":null,"abstract":"<p><p>T cell activation is an essential step in chimeric Ag receptor (CAR) T (CAR T) cell manufacturing and is accomplished by the addition of activator reagents that trigger the TCR and provide costimulation. We explore several T cell activation reagents and examine their effects on key attributes of CAR T cell cultures, such as activation/exhaustion markers, cell expansion, gene expression, and transduction efficiency. Four distinct activators were examined, all using anti-CD3 and anti-CD28, but incorporating different mechanisms of delivery: Dynabeads (magnetic microspheres), TransAct (polymeric nanomatrix), Cloudz (alginate hydrogel), and Microbubbles (lipid membrane containing perfluorocarbon gas). Clinical-grade lentiviral vector was used to transduce cells with a bivalent CD19/CD22 CAR, and cell counts and flow cytometry were used to monitor the cells throughout the culture. We observed differences in CD4/CD8 ratio when stimulating with the Cloudz activator, where there was a significant skewing toward CD8 T cells. The naive T cell subset expressing CD62L+CCR7+CD45RA+ was the highest in all donors when stimulating with Dynabeads, whereas effector/effector memory cells were highest when using the Cloudz. Functional assays demonstrated differences in killing of target cells and proinflammatory cytokine secretion, with the highest killing from the Cloudz-stimulated cells among all donors. This study demonstrates that the means by which these stimulatory Abs are presented to T cells contribute to the activation, resulting in differing effects on CAR T cell function. These studies highlight important differences in the final product that should be considered when manufacturing CAR T cells for patients in the clinic.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appropriate Sampling and Longer Follow-Up Are Required to Rigorously Evaluate Longevity of Humoral Memory After Vaccination.","authors":"Vitaly V Ganusov","doi":"10.4049/immunohorizons.2300057","DOIUrl":"10.4049/immunohorizons.2300057","url":null,"abstract":"<p><p>One of the goals of vaccination is to induce long-lived immunity against the infection and/or disease. Many studies have followed the generation of humoral immunity to SARS-CoV-2 after vaccination; however, such studies typically varied by the duration of the follow-up and the number of time points at which immune response measurements were done. How these parameters (the number of time points and the overall duration of the follow-up) impact estimates of immunity longevity remain largely unknown. Several studies, including one by Arunachalam et al. (2023. J. Clin. Invest. 133: e167955), evaluated the humoral immune response in individuals receiving either a third or fourth dose of mRNA COVID-19 vaccine; by measuring Ab levels at three time points (prior to vaccination and at 1 and 6 mo), Arunachalam et al. found similar half-life times for serum Abs in the two groups and thus suggested that additional boosting is unnecessary to prolong immunity to SARS-CoV-2. I demonstrate that measuring Ab levels at these three time points and only for 6 mo does not allow one to accurately evaluate the long-term half-life of vaccine-induced Abs. By using the data from a cohort of blood donors followed for several years, I show that after revaccination with vaccinia virus, vaccinia virus-specific Abs decay biphasically, and even the late decay rate exceeds the true slow loss rate of humoral memory observed years prior to the boosting. Mathematical models of Ab response kinetics, parameterized using preliminary data, should be used for power analysis to determine the most appropriate timing and duration of sampling to rigorously determine the duration of humoral immunity after vaccination.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncommon P1 Anchor-featured Viral T Cell Epitope Preference within HLA-A*2601 and HLA-A*0101 Individuals.","authors":"Jianing Zhang, Can Yue, Yin Lin, Jinmin Tian, Yuanyuan Guo, Danni Zhang, Yaxin Guo, Beiwei Ye, Yan Chai, Jianxun Qi, Yingze Zhao, George F Gao, Zeyu Sun, Jun Liu","doi":"10.4049/immunohorizons.2400026","DOIUrl":"10.4049/immunohorizons.2400026","url":null,"abstract":"<p><p>The individual HLA-related susceptibility to emerging viral diseases such as COVID-19 underscores the importance of understanding how HLA polymorphism influences peptide presentation and T cell recognition. Similar to HLA-A*0101, which is one of the earliest identified HLA alleles among the human population, HLA-A*2601 possesses a similar characteristic for the binding peptide and acts as a prevalent allomorph in HLA-I. In this study, we found that, compared with HLA-A*0101, HLA-A*2601 individuals exhibit distinctive features for the T cell responses to SARS-CoV-2 and influenza virus after infection and/or vaccination. The heterogeneous T cell responses can be attributed to the distinct preference of HLA-A*2601 and HLA-A*0101 to T cell epitope motifs with negative-charged residues at the P1 and P3 positions, respectively. Furthermore, we determined the crystal structures of the HLA-A*2601 complexed to four peptides derived from SARS-CoV-2 and human papillomavirus, with one structure of HLA-A*0101 for comparison. The shallow pocket C of HLA-A*2601 results in the promiscuous presentation of peptides with \"switchable\" bulged conformations because of the secondary anchor in the median portion. Notably, the hydrogen bond network formed between the negative-charged P1 anchors and the HLA-A*2601-specific residues lead to a \"closed\" conformation and solid placement for the P1 secondary anchor accommodation in pocket A. This insight sheds light on the intricate relationship between HLA I allelic allomorphs, peptide binding, and the immune response and provides valuable implications for understanding disease susceptibility and potential vaccine design.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}