bluuebunny/crossref_metadata_2025_split huggingface dataset:
The XS106 cell line: profile of TLR ligand responses reveals a Langerhans cell-like phenotype (102.7)
Authors: Dearman Rebecca , Eaton Laura , Kimber Ian 
Published: January 2023

Abstract
The XS106 dendritic cell (DC) line, isolated from the epidermis of newborn A/J mice, has been characterized with respect to membrane marker expression and responsiveness to Toll like receptor (TLR) ligand (lipopolysaccharide [LPS], peptidoglycan [PGN], CpG, flagellin, R848) activation. Resting XS106 cells were positive for MHC class II, CD80, CD86, CD40, CD11c, CD11b and CD103 but did not express detectable Langerin or EpCAM. Cells expressed constitutively high levels of type 2-associated chemokines CCL17 and CCL22 but little of the type 1-associated chemokines CXCL9 and CXCL10. Stimulation (24h) with LPS, flagellin and PGN markedly up-regulated membrane marker and CCL17 and CCL22 expression, whereas both CpG and R-848 were without significant effect. Enhanced type 1 chemokine expression was inducible by culture with recombinant interferon-γ. Using a functional assay, cells migrated towards CXCL12, but not to CCL19 (ligands promoting migration to the dermis and lymph nodes, respectively). Migration was abrogated if cells were activated with LPS or PGN, but not CpG. Thus, XS106 cells have a relatively immature DC membrane marker phenotype which is not identical to that reported for either of the main skin DC populations (Langerhans cells (LC) or dermal (d)DC). The TLR ligand response pattern shows that XS106 are similar to LC and dDC with regard to their preferential type 2 chemokine profile and their pattern of migration is LC-like.
Dendritic cells elicit allergic immune responses in a CCR7-dependent fashion (103.10)
Authors: Saban Daniel , Schlereth Simona , Lee Hyunsoo 
Published: January 2023

Abstract
DCs are key in mounting allergic immunity by mobilizing from allergen exposed sites to lymphoid tissues for T cell activation. However, whether the CCR7-CCL19/21 axis promotes DC mobilization and Th2 responses in allergy is incompletely understood. We thus sought to determine if CCR7 expression by DCs promotes allergy. Allergic conjunctivitis (AC) was evaluated in wild-type (WT) mice immunized via adoptive transfer with OVA/Alum-primed (WT) T cells. Mice were injected subconjunctivally (SCJ) with exogenous WT or CCR7 KO DCs (or PBS), and immediately instilled with OVA-loaded eye drops to induce AC. Clinical signs were scored biomicroscopically, and sera were sampled for OVA-specific IgE analysis. T cells were isolated for cytokine analyses to in vitro recall stimulation. Lastly, leukocytosis of collagenase-digested conjunctival cells was FACS analyzed. Upregulated CCR7 expression was confirmed of SCJ injected WT DCs found in lymph nodes of immunized mice following instillation of PE-OVA eye drops. Mice with WT DCs showed significant augmentation of clinical signs relative to sham controls. This was corroborated by a 2-fold increase in mast cell and eosinophil infiltration, 4-fold increase in IL-13 and IL-4, and an 8-fold increase in IgE (p&lt;0.05). Strikingly, this augmentation was completely reversed in hosts with CCR7 KO DCs, and this abrogation was consistently seen in all parameters. Thus, our study suggests that DCs promote allergic immunity in a CCR7-dependent fashion.
Galectin-3 modulates T helper responses by regulating dendritic cell cytokine expression (103.11)
Authors: Fermin Agnes , Chen Huan-Yuan , Hsu Daniel , Wang Li Chieh , Wan Lei , Liu Fu-Tong 
Published: January 2023

Abstract
Dendritic cells play a critical role in the initiation and maintenance of inflammatory responses. Galectin-3, a protein found in DCs, is a carbohydrate-binding protein implicated in several cellular processes. In mouse models of asthma and atopic dermatitis, galectin-3-deficient (gal3-/-) mice had significantly fewer infiltrating eosinophils and displayed lower Th2 but higher Th1 responses compared to wild-type mice, suggesting that galectin-3 plays a key role in allergic inflammation. Given the ability of DCs to direct the T lymphocyte response, we hypothesized that galectin-3 may affect immune responses by altering DC functions and tested the hypothesis by comparing wild-type and gal3-/- DCs. OT-II CD4+ cells cultured with OVA-pulsed gal3-/- DCs generated higher Th1 responses relative to gal3+/+ DCs, and the differences were diminished following IL-12 neutralization. Moreover, gal3-/- DCs expressed more IL-12p35 mRNA than gal3+/+ DCs, indicating that gal3 may modulate IL-12 at the transcriptional level or through upstream signaling pathways. T cells co-cultured with gal3-/- DCs also secreted more IL-17 than cells cultured with gal3+/+ DCs, suggesting that gal3 may also negatively regulate Th17 responses. Furthermore, we observed higher IL-6 secretion and IL-23p19 expression in gal3-/- DCs, which may contribute to the enhanced Th17 polarization induced by these cells. We conclude that gal3 may regulate DC cytokine expression, thereby modulating T helper responses.
G0S2, an early response gene, regulates quiescence in naïve T cells (104.10)
Authors: Yamada Takeshi , Lee Ping-Hsien , Burns Audrea , Lacorazza Daniel 
Published: January 2023

Abstract
The G0/G1 switch gene 2 (G0S2) was identified in a screen using mitogen-activated human blood mononuclear cells (DNA and Cell Biology 9, 579, 1990). G0S2 is a small basic protein expressed in hematopoietic cells that is upregulated in autoimmune and inflammatory processes. However, the ability of G0S2 to control T cell proliferation has yet to be determined. We found that G0S2 transcription was suppressed following TCR activation in naïve T cells, suggesting its role in T cell quiescence. Also, inhibition of MAPK, PI3K, mTOR and Ca2+/calcineurin pathways abrogated G0S2 gene suppression, which suggests that the aforementioned pathways are involved in the suppression of G0S2. Moreover, gain-of function experiments, using retroviral gene transfer and BM transplantation, showed that ectopic G0S2 expression inhibited proliferation of T cells during homeostasis and upon TCR activation. Conversely, silencing G0S2 expression enhanced T cell proliferation, indicating that G0S2 maintains quiescence of naïve T cells. We further identified nucleolin as a protein partner of G0S2 by Co-IP and mass-spectrometry. This data suggests that G0S2 interferes with nucleolin-mediated stabilization of mRNAs of genes required for proliferation control. Collectively, our study uncovered an important role of G0S2 in the mechanism of T cell quiescence.
CD5 through CK2 activation regulates B-1a B-cell survival, proliferation, and T-independent type 2 antibody response. (104.15)
Authors: Cashman Kevin , Sestero Christine , De Sarno Patrizia , Raman Chander 
Published: January 2023

Abstract
CD5 expression is the characteristic feature of B-1a B-cells and B10 regulatory B-cells; however, the physiological role of this receptor on the development, persistence, and/or function of these B-cell populations remains undefined. To begin addressing this question we generated a CD5 mutant knock-in mouse (CD5ΔCK2BD) in which the serine threonine kinase, CK2, binding domain in the CD5-cytoplasmic tail was deleted. CD5 plays a critical role in regulating T-cell survival following antigen receptor engagement and this activity is dependent on CK2 activation. In the CD5ΔCK2BD mouse, the ability to activate CK2 is abrogated. B-1a B-cells in the CD5ΔCK2BD mouse turnover at a rate two-fold greater than that in WT mice. This increased turnover rate compensated for the decreased B-cell survival to maintain a near normal B-1a B-cell number in the peritoneal cavity. However, total serum natural IgM and IgA was significantly lower than that in WT mice. CD5ΔCK2BD B-1a B-cells proliferated poorly in response to anti-IgM stimulation but not LPS stimulation. The CD5ΔCK2BD mouse also exhibited an impaired anti-phosphatidylcholine (PC) response following immunization with heat killed S. pneumoniae, a prototypic B-1a B-cell response. Immune responses to T-independent type 1 antigen were not altered in the CD5ΔCK2BD mouse. These data provide the first evidence that CD5 has a direct role in regulating B-1a B-cell physiology.
Mechanisms of defective T cell-dependent B cell responses with age (104.17)
Authors: Yu Mingcan , Li Guangjin , Lee Won-Woo , Yuan Ming , Weyand Cornelia , Goronzy Jörg 
Published: January 2023

Abstract
The ability to generate immune responses after vaccinations declines with age. Efforts to improve vaccine responses have focused on identifying immunogenic vaccines and novel adjuvants. We hypothesized that signaling pathways in T cells can be directly targeted to optimize responses in the elderly. Gene expression profiling of CD4 memory T cell from 65 to 85 year-old compared to young adults stimulated with myeloid dendritic cells plus superantigen showed an overexpression of the dual-specific phosphatase 4 (DUSP4) on days 2 and 3 in the elderly which was confirmed by qPCR (p&lt;0.001), Western blotting (p=0.03) and DUSP4 promoter reporter gene assays (p&lt;0.001). Overexpression of DUSP4 in young T cells shortened CD40L (p&lt;0.001) and ICOS (p&lt;0.001) expression and decreased IL-4 (p&lt;0.001), IL-17A (p&lt;0.001) and IL-21 (p&lt;0.001) production. Conversely, DUSP4 silencing increased expression. Improvement was more pronounced in elderly T cells for CD40L (p&lt;0.001), IL-4 (p=0.007) and IL-21 (p=0.04). CD4 memory T cells from 65 to 85 year-old individuals failed to support differentiation of young adult B cells into CD38+IgD- B cells in vitro (p=0.004). DUSP4 silencing in CD4 T cells restored this ability (p=0.02). The role of DUSP4 expression in CD4 T cells in regulating T cell-dependent B cell responses was confirmed in in vivo studies using CD4 knockout mice reconstituted with DUSP4 overexpressing or control OT-II CD4 T cells and in healthy volunteers undergoing influenza vaccination.
Intestinal inflammation in Gimap5 deficient mice: a possible link between loss of FoxO expression and impaired Treg function (104.18)
Authors: Aksoylar Halil , Lampe Kristin , Hoebe Kasper 
Published: January 2023

Abstract
We previously identified an N-ethyl-N-nitrosourea (ENU) induced mutant, sphinx, which lacks CD8+ T cells and natural killer cells in the peripheral lymphoid organs due to a recessive mutation in Gimap5 gene. Gimap5sph/sph mice developed spontaneous intestinal inflammation that is dependent on CD4+ T cells and commensal microflora. Gimap5sph/sph CD4+ T cells displayed a progressive lymphopenia, adopted a CD44hi CD62Llow activated phenotype and produced increased levels of IL-17. Lymphopenia of CD4+ T cells was accompanied with the progressive loss of FoxO1 and FoxO3 proteins. FoxO transcription factors have recently been implicated in regulatory T cell (Treg) development and function. Here we show that Gimap5sph/sph CD4+ T cells had a selective decline of the FoxP3+ Treg subset with time. Moreover, immune suppressive capacity of Gimap5sph/sph Treg cells was impaired in correlation with the loss of FoxO proteins. Further, adoptive transfer of wild type Treg cells into Gimap5sph/sph mice prevented the development of intestinal inflammation. Together, these results show a possible link between impaired homeostasis of T cells, particularly the Treg subset and loss of FoxO proteins which leads to intestinal inflammation in the absence of Gimap5 function.
Role of MS4a4B in regulation of T cell apoptosis (104.20)
Authors: Xu Hui , Yan Yaping , Zhang Guangxian , Rostami Abdolmohamad 
Published: January 2023

Abstract
MS4a4B is a membrane protein that highly expressed in T cells. We have demonstrated previously that MS4a4B has an inhibitory role in T cell proliferation. Interestingly, a decreased level of MS4a4B is associated with apoptotic T cells. In this study, we further analyzed the role of MS4a4B in T cell proliferation and apoptosis. We co-cultured MS4a4B+ EL4 cells (GFP+) with MS4a4B- EL4 cells (GFP-) and compared cell proliferation by flow cytometry. We found that MS4a4B inhibited EL4 cell proliferation during the early stage of co-culture. However, the percentage of MS4a4B+ EL4 cells was enhanced, suggesting that MS4a4B prolonged EL4 cell survival. To determine if MS4a4B expression reduced apoptosis in EL4 cells, we analyzed apoptotic cells during MS4a4B+/MS4a4B- cell co-culture. The results showed that the apoptosis percentage in MS4a4B+ EL4 cells was markedly lower than in MS4a4B- EL4 cells. To determine whether MS4a4B protected T cells from activation-induced cell death (AICD), we knocked down MS4a4B expression in mouse T cell line (T32 cells) and primary T cells by MS4a4B shRNA vector and MS4a4B siRNA. Knockdown of MS4a4B promoted anti-CD3/anti-CD28-induced apoptosis in T32 cells and primary T cells. Machinery analysis showed that over-expression of MS4a4B decreased the activity of caspase 3/7, caspase 8 and caspase 9. Our data suggest that MS4a4B not only has an inhibitory role in T cell proliferation but also plays a role in regulation of T cell apoptosis.
Circulating antigen presenting cells in chronically infected HBV patients do not constitutively cross-present HBV antigens (105.22)
Authors: Gehring Adam , Haniffa Muzlifah , Konduru Sastry , Ginhoux Florent , Bertoletti Antonio 
Published: January 2023

Abstract
Persistent exposure to antigen is thought to play a primary role in dysfunction of virus-specific T cells in chronic infection. Our study sought to determine whether antigen presenting cells (APCs) in the blood of chronic HBV patients constitutively cross-present circulating HBV antigen to virus-specific CD8 T cells. We isolated dendritic cells, CD14 or CD16 monocytes and B cells from HLA-A2+ healthy donors and chronic HBV patients with 10^8 IU HBV DNA/ml serum. APCs were co-incubated with TCR-redirected T cells specific for HLA-A2 restricted HBc18-27 and HBs183-91 epitopes and activation was monitored by staining for IFN-γ. APCs were also stained with TCR-like antibodies specific for the same peptide/HLA-A2 complexes. We did not observe any HBc18-27- or HBs183-91-specific T cell activation following incubation with sorted healthy donor APCs. Nor did we see T cell activation after co-culture with APCs isolated from chronic HBV patient PBMCs. Staining with TCR-like antibodies confirmed that there were no detectable HBc18-27- or HBs183-91-HLA-A2 complexes constitutively present on the cell surface. IFN-γ production and TCR-like antibody staining was observed with peptide loaded APCs. Our data suggests that APCs in the peripheral blood of chronically infected patients do not constitutively cross-present antigen to virus-specific CD8 T cells and therefore may not contribute to T cell dysfunction.
Fitness costs and diversity of CTL response determine the rate of CTL escape during the acute and chronic phases of HIV infection (105.23)
Authors: Ganusov Vitaly , Goonetilleke Nilu , Liu Michael , Ferrari Guido , Shaw George , McMichael Andrew , Borrow Persephone , Korber Bette , Perelson Alan 
Published: January 2023

Abstract
Human immunodeficiency virus type 1 (HIV-1, or HIV) often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. We used single genome amplification and sequencing of complete HIV genomes to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set-point at 1 year after the infection. We found that the rate of viral escape from CTL responses in a given patient decreases dramatically from the acute infection to the viral set point. Using a novel mathematical model that tracks the dynamics of viral escape at multiple epitopes we show that a number of factors could potentially contribute to a slower escape in the chronic phase of infection, such as a decreased magnitude of epitope-specific CTL responses, an increased fitness cost of escape mutations, or an increased diversity of the CTL response. In the model, increasing the diversity of the CTL response over time can reduce the rate of viral escape from a given CTL response, particularly if CD8+ T cells compete for killing of infected cells or control virus replication non-lytically. Our mathematical framework of viral escape from multiple CTL responses can be used to predict the breadth and magnitude of HIV-specific CTL response that needs to be induced by vaccination to prevent (or reduce) viral escape following HIV infection.
Memory T cell stability in the wake of heterologous viral infections (105.35)
Authors: Che Jenny , Welsh Raymond 
Published: January 2023

Abstract
CD8 T cell memory is generally stable but can be reduced by heterologous infections. CD44hi CD8 and CD4 T cells undergo attrition early during infection with type I IFN-inducing pathogens or after exposure to toll receptor agonists. This attrition coincides with the early reduction of bona fide virus-specific CD8 and CD4 memory T cells and can explain the long-term loss in memory T cells that occurs after heterologous infection. An increase in the percentage of apoptotic cells was detected by TUNEL assay in both CD44hi CD8 and CD44hi CD4 T cells at day 3 post-infection with lymphocytic choriomeningitis virus (LCMV), a strong type I IFN inducer. Infection with LCMV significantly reduced vaccinia (VV)-specific CD8 memory T cells, which were further reduced by heterologous infection with murine cytomegalovirus (MCMV). MCMV also reduced LCMV-specific CD8 and CD4 memory T cells, but LCMV memory was not further eroded by persistent MCMV infection over a 48-week period, even though MCMV-specific memory cells increased in number due to memory inflation. This argued that the early IFN-dependent attrition had a greater effect on memory loss than did competition later on by inflating memory cells. A caveat, however, is that MCMV memory inflation was somewhat impaired by a prior LCMV infection, possibly due to reduced latent MCMV load caused by heterologous immunity. These results illustrate the dynamic nature of T cell memory in the wake of acute and persistent viral infections.
Maintenance of serological memory in virus-infected T cell-deficient mice (105.36)
Authors: Raval Forum , Lamothe Ben , Szomolanyi-Tsuda Eva 
Published: January 2023

Abstract
Many viruses can induce strong acute T cell-independent (TI) B cell responses due to their complex arrays of repetitive antigenic determinants on virions, coupled with the induction of innate cytokines, but T cell help is thought necessary for the development of long term humoral immunity in the form of long-lived plasma cells and memory B cells. However, we have found that T cell deficient (TCRbxd KO) mice persistently infected with polyomavirus (PyV) develop long-lasting high serum antiviral IgG responses, and we questioned whether these mice could generate TI B cell memory. TCR bxd KO PyV-infected mice had very low numbers of antibody secreting cells within the bone marrow compared to wild type (WT) mice. Moreover, by using a functional adoptive transfer assay, memory B cell responses were not detected in T cell deficient mice. In SCID mice reconstituted with TCRbxd KO mouse splenocytes, antiviral serum IgG gradually decreased, presumably due to a lack of supply of naïve B cells from bone marrow. In contrast, CD4 T cell deficient mice lack T cell help but have only short-lived antibody responses, perhaps due to control of persistent antigen by CD8 T cells. Therefore, we hypothesized that a high level of the persistent PyV antigen may subvert immunological tolerance and activate naïve B cell populations continuously, thereby maintaining the long-lasting IgG responses in T cell deficient mice. Here, we provide evidence for that hypothesis.
Type I Interferon produced by infected cells but not plasmacytoid dendritic cells is required for effective CD8 T cell responses and clearance of a viral infection (105.37)
Authors: Clingan Jonathan , Ostrow Kristin , Hosiawa-Meagher Karoline , Chen Zhijian , Locksley Richard , Matloubian Mehrdad 
Published: January 2023

Abstract
Following viral infection, multiple innate immune pathways can be engaged leading to the production of type I interferons (IFN) and other inflammatory mediators. Two major pathways involved in the sensing of virus include the Toll-like receptor (TLR) pathway, particularly important in plasmacytoid dendritic cells (pDC), and the mitochondrial antiviral signaling protein (MAVS) pathway, activated in infected cells. Although both of these pathways can be activated during a viral infection, the relative contribution of these pathways to the quality of adaptive immune responses and virus control in vivo is not well understood. Using the lymphocytic choriomeningitis virus (LCMV) model of infection, we show that while both the TLR and MAVS pathways become activated in pDC and infected cells, respectively, the MAVS pathway contributes more greatly to the type I IFN response, and is required for the production of a high quality CD8 T cell response. There were fewer effector CD8 T cells from MAVS-deficient mice, and these cells had altered expression of activation markers and exhibited a more exhausted phenotype. MAVS-deficient mice also exhibited delayed clearance of virus compared to wild-type mice, or mice deficient in signaling through nucleic acid sensing TLRs. These results demonstrate that although multiple pathways can be activated in response to LCMV, type I IFN derived from infected cells is crucial for an optimal CD8 T cell response and rapid control of infection.
Visualize immune responses during murine cytomegalovirus infection (105.38)
Authors: Qiu Zhijuan , Khanna Kamal 
Published: January 2023

Abstract
Cytomegalovirus (CMV) belongs to herpesviridae family, and can cause severe disease in immunocompromised individual. In the infected host CMV establishes a life-long latent infection even in the presence of concomitant anti-viral immunity. In humans and in mice, CMV infection leads to chronic clonal expansion of antigen specific CD8 and CD4 T cells, a phenomenon known as T cell inflation. The mechanisms that contribute to this phenomenon remain poorly defined. Furthermore, the source of antigen presentation to T cells during latency is not known. Here we used a combination of in-situ MHC class I tetramer staining and adoptive transfer studies to visualize the anatomy of the virus specific CD8 T cells in lymphoid and non-lymphoid organs of mice during primary and latent murine CMV (MCMV)-OVA infection. Our imaging studies revealed a complex spatial and temporal map of antigen presentation in the context of antigen specific CD8 T cell localization during acute and latent CMV infection. These data suggest that viral reactivation likely occurs intermittently and regionally within individual organs. Our studies provide important clues towards the mechanisms responsible for T cell inflation following CMV infection.