bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Role for a Melanosome Transport Signal in Accessing the MHC Class II Presentation Pathway and in Eliciting CD4+ T Cell Responses
Authors: Wang Siqun , Bartido Shirley , Yang George , Qin Jie , Moroi Yoichi , Panageas Katherine S. , Lewis Jonathan J. , Houghton Alan N. 
Published: January 2023

AbstractMelanosomal membrane proteins are frequently recognized by the immune system of patients with melanoma and vitiligo. Melanosomal glycoproteins are transported to melanosomes by a dileucine-based melanosomal transport signal (MTS). To investigate whether this sorting signal could be involved in presentation of melanosome membrane proteins to the immune system, we devised a fusion construct containing the MTS from the mouse brown locus product gp75/tyrosinase-related protein-1 and full-length OVA as a reporter Ag. The fusion protein was expressed as an intracellular membrane protein, sorted to the endocytic pathway, processed, and presented by class II MHC molecules. DNA immunization with this construct elicited CD4+ T cell proliferative responses in vivo. Ag presentation and T cell responses in vitro and in vivo required a functional MTS. Mutations of either the upstream leucine in MTS or elimination of the entire MTS negated in vitro Ag presentation and in vivo T cell responses. In a mouse melanoma model, DNA immunization with MTS constructs protected mice from tumor challenge in a CD4+ T cell-dependent manner, but complete deletion of MTS decreased tumor rejection. Therefore, MTS can target epitopes to the endocytic pathway leading to presentation by class II MHC molecules to helper T cells.
IL-15 Promotes Survival But Not Effector Function Differentiation of CD8+ TCRαβ+ Intestinal Intraepithelial Lymphocytes
Authors: Lai Yein-Gei , Gelfanov Vasily , Gelfanova Valentina , Kulik Liudmila , Chu Ching-Liang , Jeng Sheau-Wen , Liao Nan-Shih 
Published: January 2023

AbstractCD8 single-positive cells, including CD8αα+ and CD8αβ+ subsets, constitute the majority of TCRαβ+ intestinal intraepithelial lymphocytes (αβ iIEL) in mice. CD8+ αβ iIEL show significantly weaker responses to TCR stimulation in the presence of exogenous IL-2 than do CD8+ T cells of the central immune system. IL-15 is a T cell growth factor likely expressed in the intestine mucosa. To understand the role of IL-15 in CD8+ αβ iIEL biology, we compared the effects of exogenous IL-15 and IL-2 on the survival and primary responses of the two CD8+ αβ iIEL subsets in vitro. In contrast to the death of ∼60% of both CD8αα+ and CD8αβ+ iIEL cultured in IL-2 with or without TCR stimulation, IL-15 promoted survival of the CD8αα+ subset in the presence of TCR stimulation and promoted survival of both subsets in the absence of TCR stimulation. The higher proliferation level of TCR stimulated CD8αα+ αβ iIEL cultured in IL-15 compared with those cultured in IL-2 is likely due to IL-15’s prosurvival effects. In addition, unlike exogenous IL-2, exogenous IL-15 did not support the effector functions of either iIEL subsets, including IFN-γ production, IL-4-induced Th2 cytokine production, and anti-TCR mAb-redirected cytotoxicity. These findings demonstrate that IL-15 and IL-2 are functionally distinct and suggest that IL-15 plays a unique role in the maintenance of the CD8+ αβ iIEL pool in the absence of Ag stimulation and in the survival and expansion of CD8αα+ αβ iIEL upon Ag stimulation.
Distinct Proteolytic Processes Generate the C and N Termini of MHC Class I-Binding Peptides
Authors: Mo X. Y. , Cascio Paolo , Lemerise Kristen , Goldberg Alfred L. , Rock Kenneth 
Published: January 2023

AbstractMost of the MHC class I peptides presented to the immune system are generated during the course of protein breakdown by the proteasome. However, the precise role of the proteasome, e.g., whether this particle or some other protease generates the carboxyl (C) and amino (N) termini of the presented 8- to 10-residue peptides, is not clear. Here, we show that presentation on Db of ASNENMETM, a peptide from influenza nucleoprotein, and on Kb of FAPGNYPAL, a peptide from Sendai virus nucleoprotein, was blocked by the proteasome inhibitor, lactacystin. Using plasmid minigene constructs encoding oligopeptides of various lengths, we found that presentation of ASNENMETM from C-terminally extended peptides that contain this antigenic peptide plus three or five additional amino acids and presentation of FAPGNYPAL from a peptide containing FAPGNYPAL plus one additional C-terminal residue required the proteasome. In contrast, the proteasome inhibitor did not reduce presentation of cytosolically expressed ASNENMETM or FAPGNYPAL or N-terminally extended versions of these peptides, suggesting involvement of aminopeptidase(s) in trimming these N-extended variants. Accordingly, when the N termini of these 3N-extended peptides were blocked by acetylation, they were resistant to hydrolysis by cellular aminopeptidases and pure leucine aminopeptidase. Moreover, if introduced into the cytosol, Ag presentation of these peptides occurred to a much lesser extent than from their nonacetylated counterparts. Thus, the proteasome is essential for the generation of ASNENMETM and FAPGNYPAL peptides from the full-length nucleoproteins. Although it generates the C termini of these presented peptides, distinct aminopeptidase(s) can trim the N termini of these presented peptides to their proper size.
A Distinct IL-18-Induced Pathway to Fully Activate NK T Lymphocytes Independently from TCR Engagement
Authors: Leite-de-Moraes Maria C. , Hameg Agathe , Arnould Anne , Machavoine François , Koezuka Yasuhiko , Schneider Elke , Herbelin André , Dy Michel 
Published: January 2023

AbstractNK T lymphocytes are characterized by their ability to promptly generate IL-4 and IFN-γ upon TCR engagement. Here, we demonstrate that these cells can also be fully activated in the absence of TCR cross-linking in response to the proinflammatory cytokine IL-18 associated with IL-12. NK T cells stimulated with IL-18 plus IL-12 proliferated, killed Fas+ target cells, and produced high levels of IFN-γ without IL-4. In these conditions, IFN-γ production was at least 10-fold higher than that upon TCR cross-linking. Interestingly, a 2-h pretreatment with IL-12 plus IL-18 sufficed to maintain the high IFN-γ-producing potential during subsequent stimulation with anti-TCR mAbs or with the specific Ag α-galactosylceramide. Similar effects were observed in vivo, because splenic CD4+ NK T cells from MHC class II-deficient mice secreted IFN-γ without further stimulation when removed 2 h after a single injection of IL-12 plus IL-18. In conclusion, our evidence for activation of NK T lymphocytes in response to IL-18 plus IL-12 in the absence of TCR engagement together with the maintenance of preferential IFN-γ vs IL-4 production upon subsequent exposure to specific Ags is consistent with the active participation of this cell population in innate as well as acquired cellular immune responses.
Altered Donor and Recipient Ly49+ NK Cell Subsets in Allogeneic H-2d → H-2b and H-2b → H-2d Bone Marrow Chimeras
Authors: Korten Simone , Wilk Esther , Gessner J. Engelbert , Meyer Dirk , Schmidt Reinhold E. 
Published: January 2023

AbstractNK cells reject non-self hematopoietic bone marrow (BM) grafts via Ly49 receptor-mediated MHC class I-specific recognition and calibration of receptor expression levels. In this paper we investigated how Ly49+ subset frequencies were regulated dependent on MHC class I expression. The development of donor and host Ly49A+ (recognizes H-2Dd and H-2Dk ligands) and Ly49C/I+ (Ly49CBALB/c recognizes H-2Kb, H-2Kd, and H-2Dd, and Ly49CB6 recognizes only H-2Kb) NK cell frequencies were monitored for 120 days in murine-mixed allogeneic BM chimeras. C57BL/6 (H-2b) BM was transplanted into BALB/c (H-2d) mice and vice versa. Peripheral NK cell populations were examined every 5 days. Chimerism was found to be stable with 80–90% donor NK cells. In contrast to syngeneic controls reexpressing pretransplant patterns, donor and host NK cells revealed new and mainly reduced subset frequencies 55 days after allogeneic transplantation. Recipient NK cells acquired these later than donor NK cells. In H-2d → H-2b chimeras Ly49A+, Ly49C/I+, and Ly49A+/Ly49C/I+ proportions were mainly diminished upon interaction with cognate ligands. Also in H-2b → H-2d chimeras, Ly49A+ and Ly49A+/Ly49C/I+ subsets were reduced, but there was a transient normalization of Ly49C/I+ proportions in the noncognate host. After 120 days all subsets were reduced. Therefore, down-regulation of developing Ly49A+ and Ly49C/I+ chimeric NK cell frequencies by cognate ligands within 7–8 wk after BM transplantation may be important for successful engraftment.
Antigen-Experienced T Cells Undergo a Transient Phase of Unresponsiveness Following Optimal Stimulation
Authors: De Mattia Fabrizio , Chomez Susanna , Van Laethem François , Moulin Véronique , Urbain Jacques , Moser Muriel , Leo Oberdan , Andris Fabienne 
Published: January 2023

AbstractInteraction of the Ag-specific receptor of T lymphocytes with its Ag/MHC ligand can lead either to cell activation or to a state of unresponsiveness often referred to as anergy. It has been generally assumed that anergy develops as a consequence of inadequate stimulation, such as in response to altered peptide ligands or to agonists presented by costimulatory-deficient accessory cells. The present study uncovers an alternative way of inducing an unresponsive state in T cells. Indeed, we demonstrate herein that Ag-stimulation of murine CD4+ Th clones induces cellular activation, characterized by cytokine production and cell proliferation, followed by a state of transient (lasting up to 6 days) unresponsiveness to further antigenic stimulation. This state of activation-induced unresponsiveness 1) is not a consequence of inadequate costimulation, as it occurs when cells are stimulated in the presence of dendritic cells or anti-CD28 Abs; 2) develops after an optimal response to Ag; 3) is not due to cell death/apoptosis or CTLA-4 engagement; 4) down-regulates the proliferation and cytokine production of both Th1- and Th2-like clones; and 5) does not affect the early steps of signal transduction. Finally, naive T cells are not sensitive to this novel form of unresponsiveness, but become gradually susceptible to activation-induced unresponsiveness upon Ag stimulation. Collectively, these data suggest that activation-induced T cell unresponsiveness may represent a regulatory mechanism limiting the clonal expansion and effector cell function of Ag-experienced T cells, thus contributing to the homeostasis of an immune response.
Antigen-Driven Selection of TCR In Vivo: Related TCR α-Chains Pair with Diverse TCR β-Chains
Authors: Mikszta John A. , McHeyzer-Williams Louise J. , McHeyzer-Williams Michael G. 
Published: January 2023

AbstractAg-driven selection mediates effective T cell help and the development of Th cell memory in vivo. To analyze the dynamics of interclonal competition during the selection process in vivo, we use the I-Ek-restricted murine response to pigeon cytochrome c (PCC). The dominant PCC-specific clonotype expresses Vα11Vβ3 V regions with preferred sequence features in the third hypervariable regions (CDR3). In the current study we define and quantitatively monitor four subdominant PCC-specific clonotypes that express Vα11 paired with non-Vβ3 TCR β-chains (Vβ6, Vβ8.1/8.2, Vβ8.3, and Vβ14). The subdominant clonotypes emerge with similar dynamics to the dominant clonotype and together amount to similar numbers as the dominant clonotype in vivo. These subdominant clonotypes do not efficiently enter germinal centers, although they enter the memory compartment and rapidly re-emerge upon secondary challenge. Analysis of CDR3 diversity in the TCR α-chains identifies many preferred sequence features expressed by the dominant clonotype. These studies quantitatively demonstrate selection for diverse Th cells in vivo and highlight TCR α-chain dominance in Ag-driven selection for best fit.
A New Monoclonal Antibody Detects a Developmentally Regulated Mouse Ecto-ADP-Ribosyltransferase on T Cells: Subset Distribution, Inbred Strain Variation, and Modulation Upon T Cell Activation
Authors: Koch-Nolte Friedrich , Duffy Ted , Nissen Marion , Kahl Sarah , Killeen Nigel , Ablamunits Vitaly , Haag Friedrich , Leiter Edward H. 
Published: January 2023

AbstractADP-ribosylation of membrane proteins on mouse T cells by ecto-ADP-ribosyltransferase(s) (ARTs) can down-regulate proliferation and function. The lack of mAbs against mouse ARTs has heretofore prevented analysis of ART expression on T cell subsets. Using gene gun technology, we immunized a Wistar rat with an Art2b expression vector and produced a novel mAb, Nika102, specific for ART2.2, the Art2b gene product. We show that ART2.2 is expressed as a GPI-anchored protein on the surface of mature T cells. Inbred strain-dependent differences in ART2.2 expression levels were observed. C57BL/6J and C57BLKS/J express the Ag at high level, with up to 70% of CD4+ and up to 95% of CD8+ peripheral T cells expressing ART2.2. CBA/J and DBA/2J represent strains with lowest expression levels. T cell-deficient mice and NZW/LacJ mice with a defective structural gene for this enzyme were ART2.2 negative. In the thymus, ART2.2 expression is restricted to subpopulations of mature cells. During postnatal ontogeny, increasing percentages of T cells express ART2.2, reaching a peak at 6–8 wk of age. Interestingly, ART2.2 and CD25 are reciprocally expressed: activation-induced up-regulation of CD25 is accompanied by loss of ART2.2 from the cell surface. Nika102 thus defines a new differentiation/activation marker of thymic and postthymic T cells in the mouse and should be useful for further elucidating the function of the ART2.2 cell surface enzyme.
TCR α-Chain Repertoire in pTα-Deficient Mice Is Diverse and Developmentally Regulated: Implications for Pre-TCR Functions and TCRA Gene Rearrangement
Authors: Mancini Stéphane , Candéias Serge M. , Fehling Hans Jorg , von Boehmer Harald , Jouvin-Marche Evelyne , Marche Patrice N. 
Published: January 2023

AbstractPre-TCR expression on developing thymocytes allows cells with productive TCRB gene rearrangements to further differentiate. In wild-type mice, most TCRA gene rearrangements are initiated after pre-TCR expression. However, in pTα-deficient mice, a substantial number of αβ+ thymocytes are still produced, in part because early TCR α-chain expression can rescue immature thymocytes from cell death. In this study, the nature of these TCR α-chains, produced and expressed in the absence of pre-TCR expression, have been analyzed. We show, by FACS analysis and sequencing of rearranged transcripts, that the TCRA repertoire is diverse in pTα−/− mice and that the developmental regulation of AJ segment use is maintained, yet slightly delayed around birth when compared with wild-type mice. We also found that T cell differentiation is more affected by pTα inactivation during late gestation than later in life. These data suggest that the pre-TCR is not functionally required for the initiation and regulation of TCRA gene rearrangement and that fetal thymocytes are more dependent than adult cells on pTα-derived signals for their differentiation.
Effect of Anti-B7-1 and Anti-B7-2 mAb on Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease
Authors: Inoue Atsushi , Koh Chang-Sung , Yamazaki Masashi , Yagita Hideo 
Published: January 2023

AbstractWe examined the role of B7-1 and B7-2, costimulatory molecules critical to full activation of T cells, in the development of Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment with mAbs to B7-1 resulted in significant suppression of the development of this disease both clinically and histologically. In mice treated with these mAbs, the production of TNF-α and IFN-γ in the spleen cells was decreased. The delayed-type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. In contrast, treatment with Abs to B7-2, resulted in no effect on TMEV-IDD. These data suggest that B7-1 is critically involved in the pathogenesis of TMEV-IDD and that Abs to B7-1 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis.
BALB/c Mice Produce Blister-Causing Antibodies Upon Immunization with a Recombinant Human Desmoglein 3
Authors: Fan Ji-Lao , Memar Omeed , McCormick Daniel J. , Prabhakar Bellur S. 
Published: January 2023

AbstractPemphigus vulgaris (PV) is an Ab-mediated autoimmune blistering disease of mucotaneous surfaces. Over 95% of the patients with PV express DR4 or DRw6, and the disease is characterized by the presence of autoantibodies directed against desmoglein 3 (Dsg 3), a protein expressed on keratinocytes. An appropriate animal model is required to understand immunoregulation and to address the role of immunogenetic components in the production of pathogenic Abs that are characteristic of PV. Therefore, we turned to the development of a mouse model. Four strains of female mice (BALB/c, DBA/1, SJL/J, and HRS/J) were screened for their ability to produce pathogenic anti-Dsg 3 Abs. We demonstrated that only BALB/c mice immunized with a full-length Dsg 3 can produce pathogenic Abs capable of causing acantholysis of human foreskin in culture and blistering in neonatal mice. This observation suggested that either H-2d or the BALB background contains the immunogenetic makeup necessary for the production of pathogenic anti-Dsg 3 Abs. No correlation was noted between a given isotype and the pathogenic potential of autoantibodies from different strains of mice. Similarly, the pattern of reactivity of Abs with a panel of 46 synthetic peptides that span the entire Dsg 3 failed to reveal any association between binding specificity and the pathogenic potential, and suggested that pathogenic Abs might recognize conformational epitopes. Moreover, our studies showed that the epitopes recognized by pathogenic Abs are contained within the extracellular Dsg 3.
WASP Levels in Platelets and Lymphocytes of Wiskott-Aldrich Syndrome Patients Correlate with Cell Dysfunction
Authors: Shcherbina Anna , Rosen Fred S. , Remold-O’Donnell Eileen 
Published: January 2023

Abstract
Wiskott-Aldrich syndrome, an inherited blood cell disorder due to mutations of the X-chromosome gene WASP (Wiskott-Aldrich syndrome protein), was characterized originally by thrombocytopenia, immunodeficiency, and eczema. Whereas platelet dysfunction is severe and consistent, immune defects are clinically variable, ranging from negligible to life threatening. To understand this heterogeneity, we quantified WASP in PBMC and platelets, and also in neutrophils, of patients with diverse mutations. A surprisingly complex pattern of WASP expression found for lymphoid cells formed the basis for dividing the patient mutations into four groups. Group A have low WASP levels in PBMC and higher levels in EBV cell lines, as well as near normal WASP RNA levels (7 patients, most with mild disease), suggesting that group A WASP molecules are hypersusceptible to proteolysis. Group B have low WASP levels in PBMC and EBV cells and similar low RNA levels (2 patients, moderate disease). Group C have discordant expression: WASP-positive peripheral T cells and WASP-negative peripheral B cells and EBV cell lines (9 patients, variable disease severity). Noteworthy among group C kindred are several instances of B cell lymphomas. In group D, PBMC and EBV cell lines are WASP negative (7 patients, severe disease). In contrast to the complex lymphoid cell expression patterns, all patient platelets examined were WASP negative (18 diverse patients). WASP absence in platelets provides an apparent molecular explanation for the universally severe platelet dysfunction in this disease, and the cumulative lymphoid cell findings suggest that WASP levels play a substantial role in determining immune outcome.
The Specificity of Mammalian Spermatozoa, with Especial Reference to Electrophoresis as a Means of Serological Differentiation
Authors: Mudd Stuart , Mudd Emily B. H. 
Published: January 2023

Abstract
The literature on spermatotoxins repeatedly raises the question of the species specificity of mammalian spermatozoa (1–8); however, some authors conclude or imply that spermatozoa are, and some that they are not species specific. The reason for this discrepancy lies in part perhaps in the difficulty of obtaining quantitative estimates of the potencies of antisperm sera by the methods ordinarily used; in part perhaps the trouble has been that too few sperm species have been used, in experiments only incidental to some other purpose.1
Landsteiner and van der Scheer (10) have recently reported the tissue specificity of bull spermatozoa, which they could distinguish serologically from all somatic tissues studied. Do mammalian spermatozoa, then, like lens protein, possess tissue but not species specificity, or do they, as Dunbar has shown for plant pollens and fish spermatozoa (11) possess both tissue and species specificity? The first object of the present report is to answer the question of species specificity.
The Significance of Brucella Abortus Agglutinins in Human Serum
Authors: Carpenter C. M. , Boak Ruth , Chapman O. D. 
Published: January 2023

Abstract
The work of several investigators has shown that agglutinins specific for Brucella abortus may be demonstrated in human serum. In many cases, such antibodies are present in the serum from an individual who is showing no visible symptoms of undulant fever. Because of such findings, the diagnostic value of the agglutination test is questioned, particularly by those who have not made extensive examinations and who are not familiar with the procedure. The interpretation of the agglutination by human serum of an antigen prepared from cultures of Br. abortus demands careful scrutiny. We, therefore, considered it very important to obtain definite information regarding the following questions. Are the agglutinins specific for Br. abortus, Br. melitensis or some other closely related specie?Is the presence of abortus agglutinins in human serum caused by an infection with Br. abortus from which the individual has recovered?
The adaptor molecule MyD88 directly promotes CD8 T cell responses to vaccinia virus (128.12)
Authors: Zhao Yuan , Trez Carl De , Flynn Rachel , Ware Carl , Croft Michael , Salek-Ardakani Shahram 
Published: January 2023

Abstract
Vaccinia Virus (VACV) elicits a robust CD8 T cell response that plays an important role in protection. To date, there is little information on the molecules that are essential to generate large pools of VACV-specific CD8 T cells. Here we show that the adaptor molecule myeloid differentiation primary-response gene 88 (MyD88) is critical for the magnitude of primary CD8 T cell responses to both dominant and subdominant VACV epitopes, with MyD88-/- mice exhibiting profoundly reduced CD8 T cell expansion and anti-viral cytokine production. Interestingly, the defect was not due to impaired antigen-presenting cell function. MyD88-/- DC matured normally and were able to promote strong CD8 T cell priming following VACV infection. Rather, adoptive transfer experiments demonstrated that MyD88-dependent pathways in CD8 T cells were critical. MyD88-deficient CD8 T cells were defective in surviving in wild-type hosts, and poor expansion of MyD88-deficient VACV-specific CD8 T cells resulted after virus infection. In contrast, no defect was evident in the absence of TRIF, TLR2, TLR9, and IL-1R. Together, our results highlight an important role for MyD88 in initial anti-viral CD8 T cell responses and suggest that targeting this pathway may be useful in promoting and sustaining anti-VACV immunity. This work was supported by NIH grants AI77079 to S.S.A and AI67341 to M.C.