bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-Specific Cytotoxic Cell Frequencies Measured Directly Ex Vivo by the Lysispot Assay Can Be Higher or Lower Than the Frequencies of IFN-γ-Secreting Cells: Anti-HIV Cytotoxicity Is Not Generally Impaired Relative to Other Chronic Virus Responses
Authors: Snyder-Cappione Jennifer E. , Divekar Anagha A. , Maupin Genny M. , Jin Xia , Demeter Lisa M. , Mosmann Tim R. 
Published: April 2014

Abstract
CD8+ T cells in HIV-infected patients are believed to contribute to the containment of the virus and the delay of disease progression. However, the frequencies of HIV-specific CD8+ T cells, as measured by IFN-γ secretion and tetramer binding, often do not correlate with a delay in disease progression during chronic infection. Using the Lysispot and ELISPOT assays, we measured the frequencies of cytotoxic and IFN-γ-secreting T cells responding to overlapping peptides from Gag, Nef, Env, and Pol consensus HIV-1 clade B sequences. PBMC from the majority of HIV-infected subjects have significant frequencies of HIV-specific cells that killed targets within 5 h directly ex vivo. The relative frequencies of IFN-γ-secreting and cytotoxic cells varied markedly between different HIV peptide pools within the same patient, and some T cells lysed targets without secreting IFN-γ. These results indicate that measurement of IFN-γ production alone may be insufficient to evaluate the breadth of the HIV-specific T cell response. Also, neither the CTL to IFN-γ ratios nor the ex vivo CTL frequencies specific for different HIV proteins were consistently lower than responses specific for two other chronic viral infections, human CMV and EBV, within the same subjects. Thus ex vivo cytotoxic T cell frequencies do not provide evidence for a model of “preterminal differentiation” of HIV-specific CD8+ T cells during chronic HIV infection. Analysis of the frequency of directly cytotoxic HIV-specific T cells may be of considerable value in the assessment of disease progression and the potential efficacy of HIV vaccines.
Cutting Edge: Diminished T Cell TLR Expression and Function Modulates the Immune Response in Human Filarial Infection
Authors: Babu Subash , Blauvelt Carla P. , Kumaraswami V. , Nutman Thomas B. 
Published: April 2014

Abstract
Patent lymphatic filariasis is characterized by profound Ag-specific T cell hyporesponsiveness with impaired IFN-γ and IL-2 production. Because T cells have been shown to express a number of TLR and to respond to TLR ligands, we hypothesized that diminished T cell TLR function could partially account for the T cell hyporesponsiveness in filariasis. T cells expressed TLR1, TLR2, TLR4, and TLR9, and the baseline expression of TLR1, TLR2, and TLR4, but not TLR9 was significantly lower in T cells of the filarial-infected individuals compared with the uninfected individuals (both endemic and nonendemic). TLR function was significantly diminished in the T cells of filarial-infected individuals based on decreased T cell activation/cytokine production in response to TLR ligands. Thus, diminished expression and function of T cell TLR is a novel mechanism underlying T cell immune tolerance in lymphatic filariasis.
Cutting Edge: Enhanced Pulmonary Clearance of Pseudomonas aeruginosa by Muc1 Knockout Mice
Authors: Lu Wenju , Hisatsune Akinori , Koga Takeshi , Kato Kosuke , Kuwahara Ippei , Lillehoj Erik P. , Chen Wilbur , Cross Alan S. , Gendler Sandra J. , Gewirtz Andrew T. , Kim K. Chul 
Published: April 2014

Abstract
MUC1 (MUC1 in human and Muc1 in nonhumans) is a membrane-tethered mucin that interacts with Pseudomonas aeruginosa (PA) through flagellin. In this study, we compared PA pulmonary clearance and proinflammatory responses by Muc1−/− mice with Muc1+/+ littermates following intranasal instillation of PA or flagellin. Compared with Muc1+/+ mice, Muc1−/− mice showed increased PA clearance, greater airway recruitment of neutrophils, higher levels of TNF-α and KC in bronchoalveolar lavage fluid, higher levels of TNF-α in media of flagellin-stimulated alveolar macrophages, and higher levels of KC in media of tracheal epithelial cells. Knockdown of MUC1 enhanced flagellin-induced IL-8 production by primary human bronchial epithelial cells. Expression of MUC1 in HEK293T cells attenuated TLR5-dependent IL-8 release in response to flagellin, which was completely ablated when its cytoplasmic tail was deleted. We conclude that MUC1/Muc1 suppresses pulmonary innate immunity and speculate its anti-inflammatory activity may play an important modulatory role during microbial infection.
Cutting Edge: Elimination of an Endogenous Adjuvant Reduces the Activation of CD8 T Lymphocytes to Transplanted Cells and in an Autoimmune Diabetes Model
Authors: Shi Yan , Galusha Shelly A. , Rock Kenneth L. 
Published: April 2014

Abstract
The generation of adaptive immune responses is thought to require the presence of adjuvants. Although microbial adjuvants are well characterized, little is known about what provides the adjuvant effect in responses to transplanted cells or in autoimmune diseases. It had been postulated that, in these situations, injured cells instead released “endogenous adjuvants.” We previously identified uric acid as an endogenous adjuvant for coinjected Ags. We now report that elimination of uric acid reduced the generation of CTL to an Ag in transplanted syngeneic cells and the proliferation of autoreactive T cells in a transgenic diabetes model. In contrast, uric acid depletion did not reduce the stimulation of T cells to mature APCs or when endogenous APCs were activated with anti-CD40 Ab. These findings support the concept that danger signals contribute to the T cell responses to cell-associated Ags by activating APCs and identify uric acid as one of these signals.
Cutting Edge: B and T Lymphocyte Attenuator and Programmed Death Receptor-1 Inhibitory Receptors Are Required for Termination of Acute Allergic Airway Inflammation
Authors: Deppong Christine , Juehne Twyla I. , Hurchla Michelle , Friend Lindzy D. , Shah Dulari D. , Rose Christine M. , Bricker Traci L. , Shornick Laurie P. , Crouch Erika C. , Murphy Theresa L. , Holtzman Michael J. , Murphy Kenneth M. , Green Jonathan M. 
Published: April 2014

Abstract
T cell activation is regulated by coordinate interaction of the T cell Ag receptor and costimulatory signals. Although there is considerable insight into processes that regulate the initiation of inflammation, less is known about the signals that terminate immune responses. We have examined the role of the inhibitory receptors programmed death receptor-1 and B and T lymphocyte attenuator in the regulation of allergic airway inflammation. Our results demonstrate that there is a temporally regulated expression of both the receptors and their ligands during the course of allergic airway inflammation. Following a single inhaled challenge, sensitized wild-type mice exhibit peak inflammation on day 3, which resolves by day 10. In contrast, mice deficient in the expression of programmed death receptor-1 or B and T lymphocyte attenuator have persistent inflammation out to 15 days following challenge. Thus, these receptors are critical determinants of the duration of allergic airway inflammation.
Phenotypic and Functional Similarity of Gut Intraepithelial and Systemic T Cells in a Teleost Fish
Authors: Bernard David , Six Adrien , Rigottier-Gois Lionel , Messiaen Sébastien , Chilmonczyk Stefan , Quillet Edwige , Boudinot Pierre , Benmansour Abdenour 
Published: April 2014

AbstractGut-associated lymphocytes were described in fish, but their involvement in immune responses is still unknown. In rainbow trout, intraepithelial lymphocytes (IELs) are scattered between gut epithelial cells, but neither Peyer’s patches nor mesenteric lymph nodes were identified. Rainbow trout IELs contain mainly T cells, because they expressed transcripts of T cell marker homologs of CD8, CD4, CD28, CD3ε, TCRζ, TCRγ, and TCRβ and lacked IgM. However, trout IELs did not show specific homing to the gut mucosa, which in mammals defines IELs as a distinctive mucosal population. A detailed analysis of the TCRβ repertoire of rainbow trout IELs was performed in both naive and virus-infected animals. TCRβ transcripts of rainbow trout IELs were highly diverse and polyclonal in adult naive individuals, in sharp contrast with the restricted diversity of IEL oligoclonal repertoires described in birds and mammals. Significant modifications of the trout IEL TCRβ repertoire were observed after a systemic infection with a fish rhabdovirus and were especially marked for Vβ4-bearing receptors as previously reported for spleen cells. Thus, we could not find any specific properties of the trout IEL TCRβ repertoire compared with the spleen and pronephros TCRβ repertoire, which questions the reality of a distinct IEL compartment in teleosts. Our findings suggest that a highly diversified αβ ΤCR repertoire is maintained in fish IELs in the absence of Peyer’s patches and mesenteric lymph nodes, whereas the restricted diversity of mouse αβ IELs is attributed to multiple cycles of activation and recirculation, allowing a progressive narrowing of the repertoire.
Apoptotic Death Concurrent with CD3 Stimulation in Primary Human CD8+ T Lymphocytes: A Role for Endogenous Granzyme B
Authors: Laforge Mireille , Bidère Nicolas , Carmona Sylvie , Devocelle Aurore , Charpentier Bernard , Senik Anna 
Published: April 2014

Abstract
We exposed primary CD8+ T cells to soluble CD3 mAb plus IL-2 and limited numbers of monocytes (3%). These cells were activated but concurrently subjected to ongoing apoptosis (∼25% were apoptotic from day 2 of culture). However, their costimulated CD4+ counterparts were much less prone to apoptosis. The apoptotic signaling pathway bypassed Fas and TNFRs, and required the activity of cathepsin C, a protease which performs the proteolytic maturation of granzyme (Gr) A and GrB proenzymes within the cytolytic granules. Silencing the GrB gene by RNA interference in activated CD8+ T cells prevented the activation of procaspase-3 and Bid, and indicated that GrB was the upstream death mediator. A GrB-specific mAb immunoprecipitated a ∼70-kDa molecular complex from cytolytic extracts of activated CD8+ (but not resting) T cells, that was specifically recognized by a nucleocytoplasmic protease inhibitor 9 (PI-9) specific mAb. This complex was also detected after reciprocal immunoprecipitation of PI-9. It coexisted in the cytosol with the 32-kDa form of GrB. As neither were detected in the cytosol of CD4+ bystander T cells (which poorly synthesized GrB), and as silencing the perforin (Pf) gene had no effect in our system, endogenous GrB was likely implicated. Immunoprecipitation experiments failed to reveal Pf in the cytosol of CD8+ T cells, and only a tiny efflux of granular GrA was detected by ELISA. We propose that some GrB is released from cytolytic granules to the cytosol of CD8+ T lymphocytes upon CD3/TCR stimulation and escapes PI-9, thereby mediating apoptotic cell death.
IL-7 Is a Critical Factor in Modulating Lesion Development in Skn-Directed Autoimmunity
Authors: Staton Pamela J. , Carpenter A. Betts , Jackman Susan H. 
Published: April 2014

Abstract
In a murine model of autoimmunity targeted against the epidermal cell Ags, Skn, adoptive transfer of Skn-immune T cells to immunosuppressed recipients elicits skin lesions in areas of mild epidermal trauma. In this study, we examined peripheral regulation of Skn-induced autoreactivity disrupted by rendering the mice immunoincompetent. We found that regulation of Skn-directed autoimmunity was restored by cotransfer of normal syngeneic spleen cells at twice the concentration of Skn-immune cells and was evidenced by significantly reduced lesion severity by days 5–7 post-cotransfer compared with animals given injections of Skn-immune cells alone. Enrichment and depletion of normal CD4+ or CD8+ spleen cells and RT-PCR analysis of selected cytokines identified CD4+ cells as the regulatory cells in the cotransfer inoculum; however, significant reduction in lesion severity was observed only when there was a concomitant increase in levels of IL-7. The role of IL-7 was further supported in that mice cotransferred with Skn-immune cells plus normal spleen cells, but also treated with anti-IL-7 Ab, no longer exhibited reduced lesion severity. To determine whether IL-7 expression without normal spleen cell cotransfer could modulate lesion development, an IL-7-encoding plasmid (pCMV-Tag1-IL-7) was topically delivered to sites flanking the stressed skin site in Skn-induced autoimmune mice. Daily application of 15 μg of pCMV-Tag1-IL-7 significantly suppressed lesion severity. Our results support a mechanism for CD4+ T cells and IL-7 in contributing to the control of autoreactivity.
Protein Kinase Bα Is Required for Vesicle Trafficking and Class II Presentation of IgA Fc Receptor (CD89)-Targeted Antigen
Authors: Lang Gillian A. , Lang Mark L. 
Published: April 2014

Abstract
Ag presentation stimulates Ag-specific adaptive immune responses. FcαR (CD89)-mediated capture of IgA-bound exogenous Ag leads to efficient MHC class II Ag presentation by APCs. CD89 signaling is required for trafficking of internalized Ag to specialized multivesicular bodies known as MHC class II compartments (MIIC) and subsequent class II presentation. In the present study, we tested the hypothesis that the vesicle trafficking regulator protein kinase Bα (PKBα) is required for CD89-mediated trafficking to MIIC and Ag presentation. We observed by two independent methods (chemical inhibitors and specific RNA interference) that PKBα was required for CD89 trafficking to MIIC and class II Ag presentation. Expression of constitutively active PKBα in APCs expressing a mutant CD89 accessory signaling molecule (deficient in CD89/Ag trafficking, processing, and presentation) induced trafficking of CD89 to lamp1-containing late endocytic vesicles, but not class II-containing vesicles (MIIC), or class II Ag presentation. These studies show for the first time that PKBα is required for receptor-mediated Ag presentation and suggest the mechanism of action includes regulation of vesicle trafficking.
T Cells Lacking Immunoproteasome Subunits MECL-1 and LMP7 Hyperproliferate in Response to Polyclonal Mitogens
Authors: Caudill Christy M. , Jayarapu Krupakar , Elenich Laura , Monaco John J. , Colbert Robert A. , Griffin Thomas A. 
Published: April 2014

Abstract
Immunoproteasomes comprise a specialized subset of proteasomes that is defined by the presence of three catalytic immunosubunits: LMP2, MECL-1 (LMP10), and LMP7. Proteasomes in general serve many cellular functions through protein degradation, whereas the specific function of immunoproteasomes has been thought to be largely, if not exclusively, optimization of MHC class I Ag processing. In this report, we demonstrate that T cells from double knockout mice lacking two of the immunosubunits, MECL-1 and LMP7, hyperproliferate in vitro in response to various polyclonal mitogens. We observe hyperproliferation of both CD4+ and CD8+ T cell subsets and demonstrate accelerated cell cycling. We do not observe hyperproliferation of T cells lacking only one of these subunits, and thus hyperproliferation is independent of either reduced MHC class I expression in LMP7−/− mice or reduced CD8+ T cell numbers in MECL-1−/− mice. We observe both of these latter two phenotypes in MECL-1/LMP7−/− mice, which indicates that they also are independent of each other. Finally, we provide evidence of in vivo T cell dysfunction by demonstrating increased numbers of central memory phenotype CD8+ T cells in MECL-1/LMP7−/− mice. In summary, this novel phenotype of hyperproliferation of T cells lacking both MECL-1 and LMP7 implicates a specific role for immunoproteasomes in T cell proliferation that is not obviously connected to MHC class I Ag processing.
Rapid Demethylation of the IFN-γ Gene Occurs in Memory but Not Naive CD8 T Cells
Authors: Kersh Ellen N. , Fitzpatrick David R. , Murali-Krishna Kaja , Shires John , Speck Samuel H. , Boss Jeremy M. , Ahmed Rafi 
Published: April 2014

Abstract
DNA methylation is an epigenetic mechanism of gene regulation. We have determined that specific modifications in DNA methylation at the IFN-γ locus occur during memory CD8 T cell differentiation in vivo. Expression of the antiviral cytokine IFN-γ in CD8 T cells is highly developmental stage specific. Most naive cells must divide before they express IFN-γ, while memory cells vigorously express IFN-γ before cell division. Ag-specific CD8 T cells were obtained during viral infection of mice and examined directly ex vivo. Naive cells had an IFN-γ locus with extensive methylation at three specific CpG sites. An inhibitor of methylation increased the amount of IFN-γ in naive cells, indicating that methylation contributes to the slow and meager production of IFN-γ. Effectors were unmethylated and produced large amounts of IFN-γ. Interestingly, while memory cells were also able to produce large amounts of IFN-γ, the gene was partially methylated at the three CpG sites. Within 5 h of antigenic stimulation, however, the gene was rapidly demethylated in memory cells. This was independent of DNA synthesis and cell division, suggesting a yet unidentified demethylase. Rapid demethylation of the IFN-γ promoter by an enzymatic factor only in memory cells would be a novel mechanism of differential gene regulation. This differentiation stage-specific mechanism reflects a basic immunologic principle: naive cells need to expand before becoming an effective defense factor, whereas memory cells with already increased precursor frequency can rapidly mount effector functions to eliminate reinfecting pathogens in a strictly Ag-dependent fashion.
CD4+ Regulatory T Cells Are Spared from Deletion by Antilymphocyte Serum, a Polyclonal Anti-T Cell Antibody
Authors: Minamimura Keisuke , Gao Wenda , Maki Takashi 
Published: April 2014

Abstract
Broad T cell depletion has been used as an integral part of treatment in transplantation and autoimmune diseases. Following depletion, residual T cells undergo homeostatic proliferation and convert to memory-like T cells. In this study, we investigated the effect of T cell depletion by antilymphocyte serum (ALS), a polyclonal anti-T cell Ab, on CD4+ regulatory T cells. After ALS treatment, CD4+CD25+ T cells underwent proliferation and expressed a memory T cell marker, CD44. One week after ALS treatment, both CD25+ and CD25− T cells exhibited increased suppression of alloresponses in vitro, which waned thereafter to the levels mediated by naive CD25+ and CD25− T cells. By real-time PCR analyses, ALS treatment of CD4-deficient mice adoptively transferred with Thy1.2+CD4+CD25+Foxp3+ and Thy1.1+CD4+CD25−Foxp3− T cells resulted in the appearance of Thy1.2+CD4+CD25−Foxp3+ and Thy1.1+CD4+CD25+Foxp3+ T cells, suggesting the conversion between CD25+ and CD25− T cells. Naive CD25+ T cells expressed a higher level of intracellular Bcl-xL than CD25− T cells. Up-regulation of the Bcl-xL molecule during ALS-induced homeostatic expansion further promoted survival of CD25+ and, to a lessor degree, CD25− cells. These results indicate that CD25+ T cells are spared from ALS-mediated deletion, with some CD25+ T cells converting to CD25− T cells, and continue to exhibit regulatory activity. The concomitant presence of T cell deletion and continuous regulatory T cell activity may underlie the therapeutic effect of ALS, particularly in treatment of autoimmune diseases.
The Novel Inhibitory NKR-P1C Receptor and Ly49s3 Identify Two Complementary, Functionally Distinct NK Cell Subsets in Rats
Authors: Kveberg Lise , Bäck Camilla J. , Dai Ke-Zheng , Inngjerdingen Marit , Rolstad Bent , Ryan James C. , Vaage John T. , Naper Christian 
Published: April 2014

AbstractThe proximal region of the NK gene complex encodes the NKR-P1 family of killer cell lectin-like receptors which in mice bind members of the genetically linked C-type lectin-related family, while the distal region encodes Ly49 receptors for polymorphic MHC class I molecules. Although certain members of the NKR-P1 family are expressed by all NK cells, we have identified a novel inhibitory rat NKR-P1 molecule termed NKR-P1C that is selectively expressed by a Ly49-negative NK subset with unique functional characteristics. NKR-P1C+ NK cells efficiently lyse certain tumor target cells, secrete cytokines upon stimulation, and functionally recognize a nonpolymorphic ligand on Con A-activated lymphoblasts. However, they specifically fail to kill MHC-mismatched lymphoblast target cells. The NKR-P1C+ NK cell subset also appears earlier during development and shows a tissue distribution distinct from its complementary Ly49s3+ subset, which expresses a wide range of Ly49 receptors. These data suggest the existence of two major, functionally distinct populations of rat NK cells possessing very different killer cell lectin-like receptor repertoires.
Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells
Authors: Herrin Brantley R. , Justement Louis B. 
Published: April 2014

Abstract
Analysis of hematopoietic Src homology 2 (HSH2) protein expression in mouse immune cells demonstrated that it is expressed at low levels in resting B cells but not T cells or macrophages. However, HSH2 expression is up-regulated within 6–12 h in response to multiple stimuli that promote activation, differentiation, and survival of splenic B cells. HSH2 expression is increased in response to anti-CD40 mAb, the TLR ligands LPS and CpG DNA, and B lymphocyte stimulator (BLyS), a key regulator of peripheral B cell survival and homeostasis. Stimulation of B cells with anti-CD40 mAb, LPS, CpG DNA, or BLyS has previously been shown to induce activation of NF-κB. In agreement with this finding, up-regulation of HSH2 expression in response to these stimuli is blocked by inhibitors of NF-κB activation and is potentiated by stimulation with PMA, suggesting that HSH2 expression is dependent on NF-κB activation. In contrast to CD40, BAFF receptor, TLR4, and TLR9 mediated signaling, stimulation of splenic B cells via the BCR was not observed to induce expression of HSH2 unless the cells had been stimulated previously through CD40. Finally, HSH2 expression is down-regulated in splenic B cells in response to stimulation with IL-21, which has been shown to induce apoptosis, even in the presence of anti-CD40 mAb, LPS, or CpG DNA. IL-21 stimulation also results in down-regulation of antiapoptotic proteins such as Bcl-xL and up-regulation of proapoptotic proteins like Bim. Therefore, HSH2 expression is coordinately up-regulated with known antiapoptotic molecules and directly correlates with B cell survival.
Small Molecules That Enhance the Catalytic Efficiency of HLA-DM
Authors: Nicholson Melissa J. , Moradi Babak , Seth Nilufer P. , Xing Xuechao , Cuny Gregory D. , Stein Ross L. , Wucherpfennig Kai W. 
Published: April 2014

Abstract
HLA-DM (DM) plays a critical role in Ag presentation to CD4 T cells by catalyzing the exchange of peptides bound to MHC class II molecules. Large lateral surfaces involved in the DM:HLA-DR (DR) interaction have been defined, but the mechanism of catalysis is not understood. In this study, we describe four small molecules that accelerate DM-catalyzed peptide exchange. Mechanistic studies demonstrate that these small molecules substantially enhance the catalytic efficiency of DM, indicating that they make the transition state of the DM:DR/peptide complex energetically more favorable. These compounds fall into two functional classes: two compounds are active only in the presence of DM, and binding data for one show a direct interaction with DM. The remaining two compounds have partial activity in the absence of DM, suggesting that they may act at the interface between DM and DR/peptide. A hydrophobic ridge in the DMβ1 domain was implicated in the catalysis of peptide exchange because the activity of three of these enhancers was substantially reduced by point mutations in this area.