bluuebunny/crossref_metadata_2025_split huggingface dataset:
B cells promote CD4 T cell expansion and T cell mediated host defense against the fungal pathogen Pneumocystis (99.3)
Authors: Opata Michael , Garvy Beth 
Published: January 2023

Abstract
Host defense against the opportunistic fungal pathogen Pneumocystis (Pc) is dependent upon T cells, B cells and TNFα. Preliminary studies from our laboratory have demonstrated that CD4 T cells undergo increased apoptosis in the absence of B cells suggesting that B cells are critical for increased expansion and survival of Pc-specific effecter CD4 T cells. In this study, we observed increased TNFα secretion by the lymph node B cells isolated from Pc infected mice and stimulated with Pc ex vivo. B cell-derived TNFα enhanced T cells expansion in vivo and host defense against the pathogen. We further confirmed if this survival advantage elicited by B cells was through a direct or indirect contact with the CD4 T cells. We observed increased proliferation of CD4 T cells ex vivo if B cells, T cells and dentritic cells (Dcs) were co-cultured together as compared to cultures with T cells and Dcs alone. There was no difference in CD4 T cell proliferation if B cells were in direct contact with the T cells or were separated by a transwell. Taken together, our data suggests that B cells are capable of producing a soluble factor that can directly act to enhance CD4 T cell function or can indirectly increase CD4 T cell activity by enhancing the dentritic cell functions. We are currently determining whether this factor is B cell-derived TNFα, or some other soluble factor.
A synopsis of the existing knowledge of immunoreactivity against hepatitis C virus (HCV); a meta-analysis of the IEDB data (105.17)
Authors: Vaughan Kerrie , Kim Yohan , Greenbaum Jason , Peters Bjoern , Grey Howard , Sette Alessandro 
Published: January 2023

Abstract
HCV represents a major global health challenge, with ~3% of the world population infected. A large amount of immunological data related to T cell and antibody epitopes currently exists in the HCV literature, dispersed over almost 400 different scientific reports. It is therefore challenging for the scientific community to access this information in a comprehensive yet compact format. Analysis of all HCV-related epitope hosted in the IEDB, a repository of freely accessible epitope data, quantified this challenge: more than 3,300 different structures recognized by the immune system have been reported for this organism. Considering that the HCV genome itself encodes only ~3,000 amino acids in a single open reading frame, this large number likely reflects overlapping or closely related structures from the large number of HCV genotypes and quasi-species. To meet this challenge we developed a novel strategy that combines large sets of epitope data, assessing immunoreactivity by mapping structures onto reference genomes and displaying the frequency of positive responses. This allows for the simultaneous compilation and visualization of the HCV immune reactivity from hundreds of different studies, painting an unprecedented complete and complex picture of HCV immune epitope data to date. The results provide a wealth of information inventoried and cataloged for easy access by the HCV community, highlight interesting findings and underscoring areas for future study.
The role of soluble IL-7 receptor α in murine CD8+ T-cell responses (105.22)
Authors: Cote Sandra , Crawley Angela , Sad Subash , Angel Jonathan 
Published: January 2023

Abstract
The expression of membrane-bound IL-7 receptor α (CD127) is reduced in many viral infections. In HIV infection, this downregulation may be explained in part by increased plasma levels of a soluble form of CD127 (sCD127). We and others have shown that the activity of human IL-7 and cytotoxic CD8+T-cell (CTL) function is decreased by sCD127 in vitro. Observed impairment of IL-7 activity in HIV infection may contribute to the decline of CTL function. The role of sCD127 in such immunopathogenesis is not known. Determining the role of sCD127-mediated immune modulation necessitates the use of an in vivo model. The effect of sCD127 on the IL-7 response of murine splenic CD8+T-cells was evaluated. CFSE-labeled naïve CD8+T-cells were incubated with medium, IL-7 or pre-complexed IL-7 + sCD127 and cell proliferation was assessed. Unlike human T-cells, the survival of murine T-cells in vitro is dependent on the addition of γ-chain receptor cytokines to the culture medium. Cells cultured with sCD127 + IL-7 were less viable and proliferated less (as measured by cell division) compared to IL-7 alone. Our results indicate that sCD127 inhibits the activity of IL-7 on murine naïve CD8+T-cells in vitro, confirming previous results in human T-cell culture. These data suggest that the biological activity of sCD127 on CD8+T-cells is similar between mice and humans, thus providing rationale for the further study of sCD127 in established murine models of CD8+T-cell-mediated responses to infection.
Cornea-derived DC are critical for T cell expansion following HSV-1 corneal infection (105.32)
Authors: Buela Kristine-Ann , Hendricks Robert 
Published: January 2023

Abstract
The cornea possesses a resident population of DCs, but their contribution to T cell expansion in draining lymph nodes (DLN) following corneal infection is unknown. Using CD11c-DTR-EGFP mice we were able to locally deplete cornea-resident DC (in cornea before infection) and cornea-derived DC (coming from the cornea after infection (subconjunctival DT) or systemically deplete both corneal and draining lymph node (DLN) resident DC intraperitoneal DT). Depletion of cornea-resident DC did not affect T cell expansion in the DLN. Local depletion of cornea-derived DC through 3 days post infection (dpi) abrogated early CD8+ T cell expansion at 3 dpi, but only reduced CD4+ T cell expansion by 50%. Systemic depletion through 3 dpi completely abrogated early (3 dpi) expansion of both CD4 and CD8 T cells. Depletion of cornea-derived DC through 7 dpi resulted in complete abrogation of both CD4 and CD8 T cell expansion at 7 dpi. We conclude that CD8+ T cells can only be activated by DC that derive from the cornea. CD4+ T cells can be expanded by both cornea-derived and DLN resident DC up to 3 dpi. Both CD4 and CD8+ T cell expansion is dependent on DC transport of viral proteins from the cornea after 3 dpi when free virus is presumably no longer reaching the DLN. Neither local nor systemic DC depletion beyond 7 dpi influenced the development of CD4+ T cell-mediated inflammation in the cornea, suggesting that DC are dispensable for re-stimulation of CD4+ T cells in the cornea
Hepatitis C Virus Genotype 1b Vaccine can Benefit Egyptians, where Genotype 4a prevails (105.39)
Authors: Abdelwahab Sayed , Fathy Iman , Zakaria Zainab , Waked Imam , Mahmoud Mohamed , Capone Stefania , Nicosia Alfredo , Folgori Antonella , Refaat Ahmed , Osman Ahmed , Strickland G. Thomas , Cortese Riccardo 
Published: January 2023

Abstract
Hepatitis C Virus (HCV) infection is a global health burden specially in Egypt, where HCV genotype 4a predominates. Control of HCV infection will remain a challenge until the development of an effective vaccine that protects against different genotypes. There are several HCV genotype 1 vaccines in the pipelines. Differences in antigenic structure among genotypes could make cross protection against other genotypes unlikely. To assess whether Egyptians can benefit from genotype 1-based vaccines, HCV-specific T cell responses were examined in 37 HCV genotype 4a-infected patients using an interferon gamma (IFNγ) ELISpot assay in response to 7 HCV overlapping 15mer peptide pools derived from both genotype 1b and 4a that cover most of the HCV genome. Twenty two (59%) and 16 (43%) subjects responded to at least one peptide pool derived from genotype 1b and 4a, respectively, with 39% exact match in responses. Importantly, responses in different genome segments showed ≥55% exact match in response to the pools tested except the NS5a region (25%). The average IFNγ total spot forming cells (SFC)/106 PBMC (+SE) in the responding subjects for genotype 1b and 4a was 484±89 and 544±77, respectively (p=0.6). There was no significant differences in the responses of those who resolved HCV infection or not (p=0.6). In conclusion, no significant differences were found in the T cell responses of Egyptians to genotype 1b and 4a antigens suggesting that they can benefit from a genotype 1b vaccine.
Lack of SLP-76 reduces homeostatic turnover without effecting persistence of antigen specific CD4 memory T cells (105.42)
Authors: Rodgers Evann , Wiehagen Karla , Staub Elizabeth , Maltzman Jonathan 
Published: January 2023

Abstract
CD4 memory T cells are generated in response to infection or vaccination, provide protection to the host against re-infection, and persist through a combination of enhanced survival and slow homeostatic turnover. We developed a system to study the role of tonic TCR signaling in turnover and persistence of memory cells by timed deletion of the TCR-signaling adaptor SLP-76 following acute infection. In previously published studies, SLP-76 deficient memory CD4 T cells generated by in-vitro stimulation have decreased homeostatic turnover and reduced persistence. To extend these studies and directly assess antigen-specific (AgSp) memory cells, mice were infected with lymphocytic choriomeningitis virus (LCMV) Armstrong or Listeria monocytogenes expressing GP61-80 (LM-GP61). SLP-76 was deleted 30 days post-infection, and CD4 memory T cells are identified by staining with I-Ab:GP61 tetramer. SLP-76 deficient I-Ab:GP61+ cells generated in response to either pathogen are unable to participate in recall responses and have reduced steady-state BRDU incorporation. Interestingly, despite decreased turnover, loss of SLP-76 in GP61+AgSp memory cells has no effect on persistence at 30 weeks post deletion following LCMV, and the rate of memory cell decline is fixed. These studies confirm that CD4 memory T cells rely on SLP-76 dependent signals for normal homeostatic turnover and suggest that persistence of CD4 memory subpopulations differentially require tonic TCR signaling.
ICAM-1 interactions enhance effector cell contraction and memory T cell function following acute infection. (105.5)
Authors: Cox Maureen , Bullard Daniel , Zajac Allan 
Published: January 2023

Abstract
CD8 T cell responses are critical for protection from intracellular pathogens, and one hallmark of effective CD8 T cell responses is the development of a memory T cell pool which can rapidly respond to reinfection. Interactions mediated by intercellular adhesion molecule 1 (ICAM-1) have been suggested to be critical in the formation of memory CD8 T cells, as these interactions enhance both antigenic and cytokine signals. We have investigated the effect of ICAM-1 on cellular immune responses to acute infections. Surprisingly, elevated numbers of virus-specific CD8 T cells were maintained in ICAM-1null mice following LCMV infection, and this increase in the virus-specific T cell pool represents enhanced retention of “effector-like” CD8 T cells (CD127lo KLRG-1hi IL-2-) into the memory phase of the response. The development of memory phenotype CD8 T cells (CD127hi KLRG-1lo IL-2 producing) however, was not impaired by ICAM-1 deficiency. Moreover, ICAM-1null LCMV immune mice were able to efficiently control secondary infections despite proliferative defects observed in their memory T cells. The enhanced maintenance of effector phenotype cells appears to be the result of ICAM-1 deficiency on non-T cell subsets, suggesting a role for ICAM-1 mediated interactions with the APC in programming efficient contraction of effector and proliferative potential of memory CD8 T cells.
Differential ability of H-2 class Ia genes to effectively direct anti viral immunity (105.53)
Authors: Pease Larry , Pavelko Kevin , Mendez-Fernandez Yanice , Johnson Aaron , Rodriguez Moses 
Published: January 2023

Abstract
MHC class Ia molecules are regulators of antiviral immunity and are thought to function similarly in the presentation of self and antigenic peptides to T cells. However, differences in natural polymorphisms found among class Ia loci in humans and mice indicate these genes may not function equivalently. We used transgenic mice to evaluate the equivalence of MHC Ia gene function in directing cellular immunity against the picornavirus, Theiler’s encephalomyelitis virus, and found that effective antiviral immunity was promoted by H-2D transgenes but not by H-2K in this system. Because transgenes evaluated in our study encoded the peptide binding domain of the Db antigen presenting molecule expressed in the context of the Db or Kb genetic framework, our findings indicate that structural features distinguishing these genes mapping outside of these coding sequences determine ability to direct effective viral immunity. Irrespective of which transgene was expressed, the mice developed robust anti viral T cell responses against the immunodominant TMEV epitope and the T cells were recruited to infected tissue. However, only when the Db antigen binding domain was expressed in the context of the H-2D genetic framework was virus cleared. Our findings suggest that differences in tissue specific class I gene expression at the site of infection is a key factor in this differential function of class Ia genes. Such difference could underlie natural variations in class Ia polymorphism.
Immunomodulatory potential of CD3+ CD4-CD8- double negative (DN) T cells in sooty mangabeys (105.7)
Authors: Rout Namita , Else Jim , Kaur Amitinder 
Published: January 2023

Abstract
Simian immunodeficiency virus (SIV) infection in natural hosts like sooty mangabeys (SM) is typically non-pathogenic and characterized by the absence of chronic immune activation. In contrast, SIV-infected Asian macaques, such as rhesus macaques (RM), progress to AIDS. CD3+ CD4-CD8- double negative (DN) T cells comprise &lt;5% of circulating T cells in AIDS-susceptible species such as RM, but are present at significantly higher proportions (mean 20%) in SM. To investigate the significance of this difference, we compared the phenotype and function of DN T cells in SM and RM. γδ T cells, Tregs and NKT cells accounted for &lt;15% of DN T cells in both SM and RM. SM DN T cells contained a significantly higher frequency of CXCR5-positive and CCR6-positive cells indicating ability to home to lymphoid tissue and mucosal sites of inflammation. Mitogen-stimulated DN T cells in both SM and RM were functionally similar to CD4+ T cells with regards to upregulation of CD40L and expression of Th1 (IFN-γ, IL-2), Th2 (IL-13) and Th17 (IL-17) cytokines. However, SM DN T cells produced significantly higher levels of IL-13 and IL-17, and contained significantly higher frequencies of Tregs compared to RM suggesting more potent immunomodulatory function. These data raise the possibility that the Treg and Th17 functionality of SM DN T cells are instrumental in regulating immune activation and gut mucosal integrity, features that help to prevent immunodeficiency in SIV-infected SM.
Autophagy is implicated in MHC class I antigen cross-presentation mediated by potexvirus VLP (106.10)
Authors: Hanafi Laila-Aicha , Leclerc Denis , Lapointe Rejean 
Published: January 2023

Abstract
The development of vaccination platforms capable of triggering an efficient cytotoxic-T-lymphocyte (CTL) response is a priority for eliciting a protective cellular immune response. The proposed technology is based on the use of a new adjuvant composed of a virus-like particle (VLP) with the chimeric coat protein of papaya mosaic virus (PapMV). This VLP can trigger a CTL response through MHC class I antigenic cross-presentation of inserted epitopes. We have wanted to establish the cellular pathway leading to cross-presentation by those VLP. First, we chemically inhibit different molecular path that can be important for cross-presentation. We observed that cathepsin S and autophagy are implicated in cross-presentation by PapMV VLP. Also, we localized the VLP by fluorescence microscopy in antigen presenting cells (APC). To confirm the role of autophagy, we observed its induction by LC3 western blot and microscopy. When the APC are incubated with VLP we observed an activation of autophagy by LC3 lipidation. Finally for more specific inhibition, we used shRNA against ATG5 and cathepsin S in APC. Both ATG5 and cathepsin S reduced the cross-presentation by VLP In conclusion, the cross-presentation mediated by PapMV VLP is dependant on autophagy and degradation by cathepsin S. A better understanding of this mechanism would lead to the development of an efficient vaccine platform against cancer and infectious diseases
Cryptic fate of gliadin epitopes: implication for celiac disease (P730) (106.26)
Authors: Hou Tieying , Wang Nan , Qiao Shuo-Wang , Jin Xi , Sidney John , Sollid Ludvig , Mellins Elizabeth 
Published: January 2023

Abstract
Epitopes of an intact antigen that elicit potent T cell activation are classified as immunodominant epitopes. By contrast, epitopes that fail to trigger a T cell response, but can bind to class II, are called cryptic epitopes. HLA-DM (DM), an important regulator of antigen presentation, determines the immunodominant and cryptic fate of epitopes. Notably, however, we previously reported that DM interacts weakly with HLA-DQ2 (DQ2), a genetic risk factor for celiac disease (CD). Here, using the T x B hybrid cell line, T2, transfected with DQ2 with or without higher than physiological levels of DM, we have investigated the contribution of DM in the presentation of different gliadin epitopes (VII). The presentation of digested gluten requires internal processing and was dramatically inhibited when APCs were fixed. Cells lacking DM efficiently presented all four epitopes to gliadin-specific T cells. Interestingly, cells expressing DM were significantly compromised in their ability to display the above epitopes despite the higher level of surface DQ2 in DM+ cells. We conclude that all fourgliadin peptides were DM-suppressed epitopes. We hypothesize that in vivo the inefficient interaction between DQ2 and DM influences the fate of these epitopes, changing them from cryptic to immunodominant, and inducing a gliadin-specific immune response in CD patients expressing the DQ2 allele.
Suppression of antigen presentation by the adenovirus E3-19K protein; a crystallographic analysis of E3-19K/MHC I interaction (106.37)
Authors: Li Lenong , Muzahim Yasameen , Bouvier Marlene 
Published: January 2023

Abstract
The cell-surface presentation of viral antigens by MHC class I molecules is critical for eliminating infected cells. In turn, viruses have evolved strategies to interfere with the process of antigen presentation. The adenovirus (Ad) E3-19K protein binds to and retains MHC class I molecules in the endoplasmic reticulum (ER), blocking their egress to the cell surface. We characterized for the first time interaction between Ad type 2 (Ad2) E3-19K and HLA-A2 using x-ray crystallography. Our structure to 2.1Å resolution reveals that Ad2 E3-19K interacts with the N-terminus of the α1-helix and C-terminus of the α2-helix of HLA-A2, i.e., the C-terminal end of the groove. E3-19K binds away from the opening of the groove. This mode of binding is entirely consistent with our biochemical studies of E3-19K/MHC I interaction, including the ability of E3-19K to associate with mature and immature MHC class I molecules. Importantly, the Ad2 E3-19K/HLA-A2 structure reveals how E3-19K uses it variable and conserved regions to bind to MHC I, and how it accommodates polymorphism in MHC I. Our structure also allows to understand the ability of E3-19K of different Ad serotypes and subgroups to associate with MHC I in an allele- and locus-specific manner. Overall, the Ad2 E3-19K/HLA-A2 structure reveals determinants in E3-19K that are critical for targeting MHC class I molecules. It also permits to better understand how E3-19K has evolved to subvert antigen presentation.
A CD1 lipidomic analysis determines the structures of human CD1b scaffold lipids and its function to enhance mycobacterial antigen presentation (106.43)
Authors: Huang Shouxiong , Cheng Tan-Yun , Young David , Layre Emilie , Madigan Cressida , Shires John , Cerundolo Vincenzo , Altman John , Moody Branch 
Published: January 2023

Abstract
Unlike the dominant role of one class II invariant chain peptide (CLIP) in blocking MHC class II, comparative lipidomics analysis shows that human CD1a, CD1b, CD1c and CD1d proteins bind lipids corresponding to hundreds of diverse accurate mass retention time values. Although most ions were observed in association with several CD1 proteins, ligands binding selectively to one CD1 isoform allowed the study of how differing antigen binding grooves influence lipid capture. The CD1b groove is distinguished by its unusually large volume, however, the average mass of compounds eluted from CD1b was similar to that of lipids from other CD1 proteins. Elution of small ligands from the large CD1b groove might be explained, if two small lipids bind simultaneously in the groove. In the context of the known CD1b crystal structures with scaffold lipids seated below the antigen, we also found that ligands selectively associated with CD1b lacked the hydrophilic head group, which is generally needed for antigen recognition, but interferes with scaffold function. Furthermore, we identified the scaffolds as deoxyceramides and diacylglycerols and directly demonstrated a function in augmenting presentation of a mycobacterial antigen, the short chain glucose monomycolate, to T cells. Thus, unlike MHC class II, CD1 proteins capture highly diverse ligands in the secretory pathway. CD1b has a mechanism for binding two small lipids to enhance bacterial antigen presentation and T cell activation.
NKT cells support B lymphocyte functions independently of expression of the adapter SAP. (106.45)
Authors: Detre Cynthia , Keszei Marton , Kis-Toth Katalin , Castro Wilson , Magelky Erica , Tsokos George , Wang Ninghai , Terhorst Cox 
Published: January 2023

Abstract
Patients with X-linked lymphoproliferative disease (XLP) who lack functional SLAM-associated protein (SAP) have both impaired NKT cells development and progressive agammaglobulinemia. We report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. NKT cell-dependent B cell responses were absent in SAP-/-.B6 mice that lack NKT cells. However, the small number of SAP-deficient NKT cells in SAP-/-.BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted post-development in SAPfl/fl.tgCreERT2.B6 mice. These animals have normal numbers of SAP-deficient NKT cells, which efficiently support early antibody responses in the presence of αGalCer. NKT cell help during late responses does not depend upon the NKT cell intrinsic expression of SAP, provided that the conventional T cells express the adapter, as judged by adoptive transfer experiments. Thus, SAP-dependent signaling is only critical for those NKT-helper functions that act via CD4+ T cells. We conclude that SAP expression in NKT cells is dispensable for their ability to help antibody production, which suggests that residual NKT cells might contribute to the variable dysgammaglobulinemia in XLP patients.