bluuebunny/crossref_metadata_2025_split huggingface dataset:
Memory CD4 T cells protect against influenza A virus through both an interferon gamma-dependent and multiple interferon gamma-independent mechanisms (105.31)
Authors: McKinstry Kai , Strutt Tara , Swain Susan 
Published: January 2023

Abstract
Memory CD4 T cells provide strong protection against influenza A virus (IAV), but the mechanisms and cellular interactions critical for their antiviral impact are not well described. A more complete understanding of how memory CD4 T cells contribute to viral clearance could improve T cell-based vaccine strategies aimed at protecting against both seasonal and pandemic IAV strains. Here, we show that IAV-specific Th1- and Th17-polarized memory CD4 T cells, as well as memory cells primed by IAV, protect otherwise naïve mice against lethal IAV challenge. We systematically deconstruct this protective response utilizing mice deficient for B cells, T cells, or both, to reveal multiple, distinct mechanisms of protection. First, in the absence of other T cells, memory CD4 T cells synergize with B cells to provide protection that is dependent on neutralizing antibodies but independent of characterized CD4 T cell helper functions. Second, in the absence of B cells, memory CD4 T cells synergize with CD8 T cells to promote equivalent viral clearance. These mechanisms of protection are both fully independent of interferon gamma (IFNγ) production by memory CD4 T cells. Third, in the absence of both B and CD8 T cells, memory CD4 T cells directly control IAV. Strikingly, this direct control is critically dependent on IFNγ. These results support a central role for memory CD4 T cells in orchestrating and directly participating in distinct forms of heterosubtypic immunity against IAV.
Characterization of IL-10 producing CD8 T cells that limit immune surveillance during chronic virus infection. (105.34)
Authors: Hu Zhuting , Molloy Michael , Zhang Weijun , Usherwood Edward 
Published: January 2023

Abstract
Gammaherpesvirus infection in AIDS patients is associated with severe disease. Progressive loss of CD4 T cells results in an erosion of immune surveillance, which may lead to gammaherpesvirus associated tumors. Studies by our group and others have used murine γHV-68 infection in combination with CD4 depletion to model this breakdown in immune surveillance. Mice initially control the infection, but virus reactivates after 6 weeks, indicating a lack of long-term immune surveillance. We previously showed mice had elevated IL-10 and therapeutic IL-10R blockade reduced reactivation of the virus, implicating IL-10 as a key factor suppressing immune surveillance. We identified a population of IL-10 producing CD8 T cells only in the infected mice lacking CD4 T cells but not in intact mice. Here we characterize IL-10+ CD8 T cells and elucidate how they arise in both the acute and chronic phase of the infection. In the acute phase of the infection less IL-10 producing CD8s arose in the absence of CD4 help or CD40-CD40L signaling, while in the chronic phase IL-10+ CD8s only arose in the absence of CD4 help. IL-10 producing CD8s in the chronic phase showed an anergic phenotype in terms of proliferation in vitro. In addition, they suppressed the proliferation of effector CD8 T cell in vitro. Dissection of the mechanisms involved in the generation and the function of these suppressive IL-10 producing CD8 T cells may expose new targets for therapeutic intervention for AIDS patients.
Viral acute lower respiratory infections rapidly impair CD8+ T lymphocyte functions through the PD-1/PD-L1 pathway (105.44)
Authors: Erickson John , Gilchuk Pavlo , Hastings Andrew , Tollefson Sharon , Downing Melissa , Boyd Kelli , Johnson Joyce , Joyce Sebastian , Williams John 
Published: January 2023

Abstract
Viruses are leading causes of severe acute lower respiratory infection (LRI) yet evoke incomplete immunity as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid CD8+ cytotoxic T lymphocyte (CTL) functional impairment in the respiratory tract via programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated pulmonary CTL impairment occurred as early as day 7 during human metapneumovirus or influenza virus infections. Viral antigen alone was sufficient to drive PD-1 upregulation, but PD-1 ligation by infection-induced PD-L1 was required for impairment. Therapeutic inhibition of PD-1 signaling prevented CTL impairment and reduced viral titers without exacerbating lower airway pathology. Additionally, PD-1 and PD-L1 were upregulated in the lungs of pediatric patients with severe H1N1 pandemic influenza virus or respiratory syncytial virus infections. Our results indicate that PD-1 signaling mediates CTL functional impairment rapidly at primary sites of infection due to the presence of local viral antigen and represents a conserved response against different viruses that cause serious LRI in children and adults. Therefore, the PD-1/PD-L1 pathway may represent a novel target for therapeutics and vaccine development against respiratory viruses.
Narrowing of influenza A virus specific T-cell receptor alpha and beta repertoire with increasing age (105.46)
Authors: Gil Anna , Yassai Maryam , Selin Liisa , Naumov Yuri 
Published: January 2023

Abstract
Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses changed overtime with increasing age. Here, for the first time we show that the HLA-A2-restricted IAV M158-66-specific Vα T cell repertoire was significantly narrowed leading to oligoclonal expansions including the usage of a single identical VA12 clonotype. This was the case for all 8 older donors. The VA repertoire of older individuals also had longer CDR3 regions with increased usage of alanine/glycine runs which may enhance TCR promiscuity. Collectively these results suggest that CD8 memory responses in humans to non-persistent viruses like IAV are dynamic, and become narrower with preferential retention of T cell repertoires with features of enhanced promiscuity with age.
EXPLORING THE TRANSITION OF CD4 EFFECTOR INTO MEMORY T CELLS IN RESPONSE TO LCMV INFECTION (105.50)
Authors: Spasova Darina , Surh Charles 
Published: January 2023

Abstract
CD4 T cells play an essential part in generating protective memory following an infection. The mechanism through which CD4 effector T cells turn into memory however remains elusive. Previous research has shown that targeting mTOR (the mammalian target of rapamycin), results in an extended contraction period during an infection. This extended contraction period gives a chance to a large number of effector T cells to turn into memory, resulting in a larger memory T cell population. In this study, we utilize the LCMV infection model to try to better characterize the transition of Smarta CD4 T cells from effector into memory.
Functional and structural basis of T cell recognition in autoimmune gastritis: mapping of autoantigenic peptides of the α-chain of the H/K ATPase and X-ray structure of the I-Ad/peptide complexes (106.25)
Authors: Revilleza Maria Jamela , Levin Ditza , Mage Michael , Candon Sophie , Natarajan Kannan , Rui Wang , Teyton Luc , Robinson Howard , Shevach Ethan , Margulies David 
Published: January 2023

Abstract
We have previously reported the development of mouse models of autoimmune gastritis in which BALB/c mice expressing transgenic αβ TCR, designated A23 and A51, spontaneously develop acute Th1-mediated high-penetrance and chronic Th2-mediated low penetrance forms of the disease, respectively. Using an array of synthetic mutated peptides in functional and MHC II-binding assays, we now report the core peptides recognized by each of these TCR. A23 recognizes H/K ATPase residues 633-641 (AKAIAASVG) and A51 sees 892-900 (CVGLRPQWE), both exhibiting a canonical 1, 4, 6, 9 I-Ad -binding motif. To extend these findings, we determined the X-ray crystallographic structure of complexes of I-Ad with both covalent and non-covalent peptides that stimulate the A51 TCR, and used these structures to generate a molecular model of the A23-stimulating peptide/I-Ad complex. The structural identification of peptide anchor residues in individual I-Ad binding pockets and of solvent exposed side chains as T cell epitopic residues readily explains T cell proliferation data and I-Ad/peptide off-rate measurements of the large panel of truncated, chimeric, and alanine or glycine-substituted synthetic peptides. The first structure of I-Ad in complex with an autoimmune peptide offers new insight in the general question of the structural basis of responses to self antigens.
Crystal structure of the HLA-DM / DO complex and insight into the mechanism of DM-catalyzed peptide exchange. (106.28)
Authors: Stern Lawrence , Guce Abigail , Mortimer Sarah , Yoon Taejin , Painter Corrie , Jiang Wei , Mellins Elizabeth 
Published: January 2023

Abstract
Peptide loading onto class II MHC molecules, facilitated by the non-classical MHC II protein HLA-DM, is a key step in antigen presentation. The mechanism of HLA-DM action and its modulation by HLA-DO, another non-classical MHC II protein, are unknown. In this work we investigated that mechanism using kinetics, mutagenesis, and structural approaches. In the crystal structure, HLA-DM and HLA-DO bind in a side-by-side arrangement. HLA-DO adopts an MHCII-like structure with conformational alterations near the alpha subunit 3-10 helix. Kinetic analysis demonstrates that HLA-DO acts as a competitive inhibitor of HLA-DM, and analysis of the functional effects of a panel of HLA-DM mutants indicates that HLA-DO and MHC bind to the same site on HLA-DM. These results suggest a molecular mechanism for HLA-DM action, in which DM binding to MHC II facilitates peptide release by disrupting key MHC-peptide interactions and stabilizing a peptide-receptive conformation. Both peptide-MHCII H-bonding and P1 pocket interactions are disrupted.
A peptide/MHCII conformer generated in the presence of exchange peptide is the substrate for HLA-DM editing (106.30)
Authors: Ferrante Andrea , Gorski Jack 
Published: January 2023

Abstract
The mechanism of HLA-DM (DM) activity is still unclear. We have shown that peptide release from HLA-DR (DR) in the presence of DM is dependent on the presence of an exchange peptide. However, DM also promotes a small but measurable peptide release in the absence of exchange peptide. Here we show that non-denaturing SDS-PAGE separates purified peptide/DR1 (pDR1) complexes into two conformers whose ratio is dependent on peptide KD. In the absence of an exchange peptide, DM only releases peptide from the slower migrating conformer. Upon the addition of an exchange peptide, a portion of the DM-resistant conformer can be converted to the slower migrating conformer, which in turn is DM labile. Our results indicate that exchange peptide generates a conformer of the pDR1 complex, which constitutes the intermediate for peptide exchange and is also the substrate for DM activity. The resolution of the intermediate favors the peptide with the greatest ability to fold itself and the groove into a stable, low-energy complex. However, once folded into the DM-resistant conformer, even a low affinity peptide can be presented in the absence of free peptide, increasing the peptide repertoire available for presentation.
Equal Immune Rights For All Polypeptides (106.38)
Authors: Shastri Nilabh , Chen Keling 
Published: January 2023

Abstract
Effective immune surveillance requires that MHC class I molecules display a peptide repertoire on the surface representing all cellular proteins. How the peptide repertoire can be comprehensive despite large differences in abundance and stability of individual proteins is not known. We show here that peptide presentation by MHC I molecules is strongly influenced by the pioneer round of translation (PRT) associated with nonsense mediated decay (NMD) of mRNAs. The PRT allows cells to detect and eliminate aberrant mRNAs containing premature stop codons. Inhibition of PRT by knock-down of CBP80, a unique cap-binding protein reduced peptide presentation by MHC class I molecules on the cell surface without affecting global protein synthesis. On the other hand, introduction of premature stop codons changed mRNA stability without affecting peptide presentation by MHC I on the cell surface. Thus, the pioneer round of translation could be used to derive peptides presentation by MHC I molecules to generate a comprehensive display of virtually all endogenous proteins.
Neutrophils Control the Extent and Spread of the Immune Response in a Prostaglandin Mediated Process (106.46)
Authors: Yang ChiaoWen , Unanue Emil 
Published: January 2023

Abstract
We have studied the influence of neutrophils on immune responses to protein antigens in adjuvants. Neutrophils enter lymph nodes shortly after immunization starting within the first hour and continuing for several days. By using neutrophil depleting Abs or genetically neutropenic mice we found suppressive effects of neutrophils on CD4 T cell as well as Ab responses. One of the mechanisms by which neutrophils modulated the extent of T cell response was by reducing the amount of antigen available to the APC. Neutrophil-DC interaction also affected the interaction of DC with T cells. We now found that neutrophils control the spread of T cell responses to distant lymph nodes. In the presence of neutrophils ~75% of the response is restricted to the draining node but in their absence most of the response is found in distal nodes. A critical component is the production of prostaglandin made by the entering neutrophils. Prostaglandin deficient mice or in vivo inhibition of prostaglandin production by indomethacin in the presence of neutrophil entry showed unrestricted response similar to neutropenic mice. Adoptive transfer of neutrophils treated with indomethacin or transferring neutrophils from prostaglandin deficient mice into genetically neutropenic recipients supported a role for neutrophil derived prostaglandins in restricting T cell responses in popliteal nodes. In brief neutrophils modulate the extent and the spread of T cell responses in a prostaglandin mediated process.
Initiation of TCR Phosphorylation and Signal Transduction. (106.50)
Authors: Casas Javier , Brzostek Joanna , Hoerter John , Gascoigne Nicholas 
Published: January 2023

Abstract
Recognition of antigen by the T cell receptor (TCR) is the key event for the T cell activation. The earliest molecular events in T cell recognition have not yet been fully described, and the TCR triggering mechanism remains a subject of controversy. By using supported lipid bilayers to present peptide MHC class I complexes to CD8+ cells, we can monitor the very early molecular events occurring at the immune synapse. The lipid bilayer technology mimics the signaling environment for T cell activation as determined by Ca2+ flux, total phospho-Tyr levels, and IL-2 secretion. Using TIRF/FRET microscopy we have observed an early (&gt; 1 min) interaction between CD3ζ and the coreceptor CD8 that is independent of the MHC-CD8 binding, but requires CD8 association with Lck. Later (&lt; 10 min) CD3ζ-CD8 interactions require CD8-MHC binding. This suggests that, upon antigen recognition, TCR may be initially phosphorylated by Lck not associated with coreceptor, followed by MHC dependent recruitment of CD8-Lck complexes. We are currently working on elucidating the proposed different roles of unbound and coreceptor associated Lck during the early stages of antigen recognition.
human metapneumovirus attachment protein G targets RIG-I to inhibit innate immune responses (108.11)
Authors: Bao Xiaoyong , Kolli Deepthi , Liu Tianshuang , Garofalo Roberto , Casola Antonella 
Published: January 2023

Abstract
hMPV is a recently identified paramyxovirus. It is associated with respiratory illnesses in children, adults, and immunocompromised patients. Evidence suggests that the virus may also cause repeated infection throughout life. Recent investigations in our lab identified hMPV attachment glycoprotein G as an important virulence factor, as a recombinant hMPV with G protein deleted (rhMPV-ΔG) exhibited enhanced production of important immune and antiviral mediators in airway epithelial cells as well as in primary immune cells. In this study we have identified RIG-I, a major intracellular viral RNA sensor, as the target of hMPV inhibition of cellular signaling in airway epithelial cells. G protein interacts with RIG-I and prevents its recruitment to mitochondria and interaction with the adaptor protein MAVS, necessary to activate the downstream signaling pathways leading to activation of cytokine and chemokine gene expression. Site-directed mutagenesis indicates that hMPV G cytoplasmic domain is required for the inhibitory activity, as a rhMPV in which Glu 2 or Val 3 of G is substituted with Ala recapitulates the phenotype observed with G protein deleted mutant. As rhMPV-ΔG is under consideration as potential vaccine candidate, it would be important to have a mutant virus which has no or reduced inhibitory activity and contains the fewest changes, while retaining full G protein expression, which could be important for generation of fully protective immune responses.
Asymmetric division of germinal center B cells (109.1)
Authors: Barnett Burton , Ciocca Maria , Goenka Radhika , Barnett Lisa , Wu Junmin , Laufer Terri , Burkhardt Janis , Cancro Michael , Reiner Steven 
Published: January 2023

Abstract
B cells that encode high-affinity, protective antibodies are generated in the germinal center (GC) reaction, a microanatomical structure that includes GC B cells and follicular helper T cells (TFH). The selection of GC B cells to proliferate and differentiate into plasma cells and memory B cells relies on contacts with TFH. In other instances where cells undergo external contacts, polarity cues are imparted that lead to asymmetric division. We hypothesized TFH may provide polarity cues during these interactions, in addition to mitogenic and differentiative signals, so that GC B cells may divide asymmetrically to generate diversity. Using confocal microscopy we observe that GC B cells asymmetrically segregate and unequally inherit the ancestral polarity regulator PKCζ, and the receptor for interleukin 21 (IL-21R) and Bcl6, which are responsible for initiating and maintaining the GC B cell fate, respectively. Homeostatic proliferation does not involve asymmetric divisions, while ICAM-1 and CD40 both contribute to asymmetric division of B cells in vivo and in vitro, respectively. In the absence of asymmetric division, we observe a failure to generate antibody secreting cells from GCs. Together, these data support a model where, in addition to canonical signals, GC B cells receive polarity cues from TFH that result in the unequal inheritance of fate determinants by daughter B cells, leading to divergent differentiation.
Heterogeneity of the bone marrow plasma cell pool (109.14)
Authors: Chernova Irene , Bortnick Alexandra , Allman David 
Published: January 2023

Abstract
Long-lived plasma cells (PCs) are responsible for maintaining antibody titers and are believed to populate unique survival niches in the bone marrow (BM). Current models predict that BM PCs consist chiefly of long-lived, slowly renewing cells. However, we find that more than 50% of BM PCs exhibit characteristics of recently formed PCs. These characteristics include surface expression of the canonical naïve B cell surface proteins B220 and CD19, and a 50% renewal rate of less than 3 days. Surprisingly, despite the rapid turnover rate exhibited by B220+ BM PCs, antigen-induced antibody secreting cells are found within this population for more than 100 days post-immunization. Together these data offer new insights into the cellular basis of antibody titer maintenance, and suggest that BM niches are continuously repopulated by newly generated plasma cells well after antigenic exposure.
Direct detection of IgE-switched B cells in an IgE-GFP reporter mouse reveals a germinal center pathway for the generation of IgE memory B cells and plasma cells (109.3)
Authors: Talay Oezcan , Yan Donghong , Brightbill Hans , Straney Elizabeth , Zhou Meijuan , Ladi Ena , Lee Wyne , Xu Min , Egen Jackson , Austin Cary , Wu Lawren 
Published: January 2023

Abstract
IgE antibodies are pathogenic in asthma and allergic diseases, but the in vivo biology of IgE cells is poorly understood, largely due to their low frequency and a lack of good reagents to detect them specifically. It has been proposed that IgE cells develop through a germinal center IgG1 intermediate and that IgE memory resides in the IgG1 memory B cell compartment. Here we have utilized a recently generated IgE-GFP reporter mouse that enables the direct detection of IgE-switched cells to assess in vivo IgE responses. In contrast to the IgG1-centered model of IgE switching and memory, we find that IgE cells develop through a germinal center IgE intermediate to form IgE memory B cells and plasma cells. Moreover, IgE memory B cells, as opposed to IgG1 memory B cells, constitute cellular IgE memory and respond quickly upon rechallenge to produce serum IgE. Our studies provide a new model for the in vivo biology of IgE switching and memory.
A novel role for blood endothelial cells in the development and maintenance of immune memory (110.17)
Authors: Swift Stephanie , Bassett Jennifer , Bramson Jonathan 
Published: January 2023

Abstract
Vaccination with recombinant human adenovirus serotype 5 (rHuAd5) drives a CD8+ T cell response that is dominated by effector and effector memory cells. In investigating the immunobiological mechanisms that result in this effector-skewed response, we previously showed that non-haematopoietic cells play a key role in defining the rHuAd5-elicited CD8+ T cell memory population. Furthermore, maintenance of this memory population relies upon sustained transgene expression from the adenovirus vector. While we know that following vaccination rHuAd5 drains to local lymph nodes, long-term antigen persistence occurs outside this location, since surgical removal of these nodes does not impact the nature of the memory response. Here, we show that following intramuscular vaccination, the adenovirus transgene is predominantly detected in the perinodal adipose tissue, in addition to draining lymph nodes and the muscle injection site itself. In all three locations, blood endothelial cells are the primary cell type that express the adenovirus-encoded antigen, strongly indicating that this radio-resistant cell population may have a role in presenting antigen to CD8+ T cells and ultimately in defining the memory response. Long-term antigen presentation from this cell compartment may represent a mechanism to sustain CD8+ T cell memory within the circulation and to ensure adequate protective immunity is maintained in multiple organs.