bluuebunny/crossref_metadata_2025_split huggingface dataset:
Th1 fidelity vs. Th1/Th17 plasticity are dictated in vivo by pathogen lifestyle, exogenous cytokines and prior expression of IFN-gamma (96.1)
Authors: Curtis Meredith M , Way Sing Sing , Rowell Emily , Urdahl Kevin , Wilson Christopher B 
Published: January 2023

Abstract
It is unknown whether faithful and heritable commitment of CD4 T cells to an effector lineage occurs in vivo or whether plasticity of T cells to adopt different effector functions in vivo is the norm. To address this question, we examined commitment of naïve antigen-specific CD4 T cells generated during intracellular bacterial (Listeria monocytogenes, Lm) or viral (LCMV) infections. The robust TH1-polarizing environment induced by these infections yielded memory CD4 T cells stably committed to the TH1 lineage. The intracellular lifestyle of the microbe and the resultant cytokine milieu induced in response to this lifestyle were key determinants of TH1 fidelity. Infection of wild-type mice with mutant Lm that could not escape the phagocytic vacuole and replicate in the cytosol induced CD4 T cells with a mixed TH1/ TH17 response and decreased effector lineage fidelity, as did infection with wild-type Lm of mice deficient for both IL-12 and type I IFN signaling. Thus, memory CD4 T cells generated in strong TH1-polarizing environments in vivo are strongly committed to this effector lineage. Commitment is highly dependent on innate immune cytokines induced in response to entry into and replication of Lm within the cytosol, and, as we also show, on prior expression of Ifng by these memory T cells. Supported by grants from the NIH and March of Dimes.
Differential modulation of regulatory T cell function by pro-inflammatory cytokines (96.13)
Authors: Raimondi Giorgio , Thomson Angus W 
Published: January 2023

Abstract
Little is known regarding the modulation of regulatory T cell (Treg) activity. Maturing dendritic cells (DC) secrete a cocktail of cytokines (R-cocktail) that liberates T cells from Treg suppression. IL-6 is one component, but others remain unknown. We performed microarray analysis of maturing DC and identified IL-12p40, TNFα, and Ebi3 as candidates. We developed a DC-free in-vitro suppression assay to test their function. As expected, addition of supernatant from maturing DC allowed T cells to resist suppression. Use of IL-6 increased T cell resistance significantly. Its combination with IL-12 or TNFα increased T cell resistance further. IL-12 and TNFα were interchangeable, suggesting redundant activity. The R-cocktail exerted its effect on T cells since a short pre-exposure before co-culture released them from suppression. On the other hand, Treg pre-exposure increased their suppressive capacity, indicating that the effect exerted on T cells was dominant. Unexpectedly, when we tested Ebi3, in the form of IL-27, we observed sustained Treg suppressive activity, an effect that was exerted specifically on Treg, as indicated by the pre-exposure experiment. This observation helps clarify the reported anti-inflammatory capacity of IL-27. Thus, pro-inflammatory cytokines exert distinct effects on T cells and Treg, promoting counter-balancing activities used by the immune system to finely tune its reactivity.
Tec family non-receptor tyrosine kinase ITK is important for the development of skin-specific intraepithelial T cells through regulation of their skin-homing property (96.17)
Authors: Xia Mingcan , Qi Qian , August Avery , Xiong Na 
Published: January 2023

Abstract
Proper localization of immune cells during the development is critical for their optimal functions. Murine skin-specific intraepithelial T cells (sIELs) are a unique tissue-specific innate T cell population that function in the first line of defense to maintain the local tissue integrity. The sIELs originate from their fetal thymic progenitors that specifically express canonical Vγ3+ TCR. Although it has been shown that the expression of skin-homing molecules, such as CCR10, is associated with the TCR-mediated cellular selection of the progenitors for their development into sIELs, molecules that mediate the selection-associated homing molecule expression is not fully understood. Here we report that ITK-null mice have a defective sIEL development due to impaired expression of the homing molecules in the fetal thymic sIEL progenitors. In the absence of ITK, the fetal thymic Vγ3+ cells failed to upregulate the expression of the chemokine receptors important for their thymus-exiting and skin-homing, including S1P1 and CCR10, which was associated with a gradient accumulation of the Vγ3 cells in the fetal thymus and a severe defect in their seeding of the skin. On the other hand, the ITK deficiency did not affect the TCR- or IL-15 receptor-mediated proliferation of the progenitor cells. These results indicate that ITK-mediated signaling is critical for the acquirement of proper homing property by the sIEL progenitors for their peripheral localization.
CCR6 regulates the migration and effector function of Th17 cells in the gut (96.2)
Authors: Wang Chuanwu , Kang Seung G , Lee Jee H , Kim Chang H 
Published: January 2023

Abstract
T helper cells that produce IL-17 (Th17 cells) play important roles in regulation of immunity to bacteria and fungi and can cause organ-specific inflammation. The intestine is a tissue where Th17 cells are highly enriched, but migration and trafficking receptors of Th17 cells to the intestine have been unclear. It has been established that CCR6 is the signature chemokine receptor for Th17 cells but the role of this trafficking receptor in Th17 cell trafficking to the intestine has not been determined. We report here that Th17 cells preferentially migrate to the intestine and associated-lymphoid tissues, and CCR6 is the homing receptor important for Th17 cell migration to certain tissue microenvironments of the intestine where its ligand CCL20 is highly expressed. We determined the function of CCR6 of Th17 cells by comparing the migration and effector function of Th17 cells derived from wild type and CCR6-deficient mice. CCR6-deficient Th17 cells were defective in migration to Peyer's patches and small intestine but their migration to the large intestine was normal. Surprisingly, administration of CCR6-deficient Th17 cells into severe combined immunodeficiency (SCID) mice led to excessive intestinal inflammation. Following the administration of Th17 cells, we found that Th17 cells fail to propagate in the gut in the absence of CCR6 and transdifferentiate into inflammatory Th1 cells. In addition, CCR6 deficiency led to aberrantly wide-spread effector T cells in the inflamed intestine of the SCID mice. Finally, we found that the expression of CCR6 by Th17 cells is induced by TGF-β1 but suppressed by IL-2 in vitro and in vivo. Taken together, we conclude that CCR6 is a key trafficking receptor that regulates the migration and effector function of Th17 cells in the intestine.
CC chemokine receptor 4 is required for optimal Th1 memory but not IL-17+ gamma/delta T cell effector responses during Mycobacterium bovis infection (96.5)
Authors: Chensue Stephen W. , Stolberg Valerie R. , Chiu Bo-Chin , Schmidt Brian M. , Kunkel Steven L. , Sandor Matyas 
Published: January 2023

Abstract
The CC chemokine receptor 4 (CCR4) is a widely expressed receptor that in regard to T cell biology was purported to be a Th2 restricted receptor, however recent evidence suggests that this receptor is expressed by memory/effector T cells of different subsets. In an ongoing investigation, we tested the participation of CCR4 in the response to mycobacterial pulmonary infection using C57BL/6 CCR4 knockout (CCR4-/-) mice and monitoring effector cell populations by flow cytometric detection. Initial studies indicated CCR4 agonist expression occurred in lungs following I.T. infection with 105 M. bovis BCG. Compared to CCR4+/+ controls, CCR4-/- mice displayed delayed bacterial clearance and impaired accumulation of interferon-γ (IFNγ) producing CD4+ T (Th1) cells in lungs. In contrast, IL-17+ cells which were largely γ/δ T cells were unaffected in CCR4-/- mice. The CCR4-/- appeared to generate Th1 cells normally in draining lymphoid tissue but these did not accumulate optimally in lungs. Moreover, CCR4-/- also displayed abrogated granuloma recall responses when lungs were challenged with mycobacterial Ag coated beads. These findings further support the notion that CCR4 is important for optimal Th memory responses, including Th1-mediated responses. Supported by NIH-NIAID grant AI43460.
Positive cooperativity between BCR and IL4 receptor signaling pathways. (97.13)
Authors: Aflakiyan Nooshin , Rao Kanury Venkata Subba 
Published: January 2023

Abstract
The BCR-triggered responses of mature and transitional immature B cells differ at both the biochemical and functional level. It was previously shown that BCR cross-linking in vitro results in death of early transitional (T1) immature B cells whereas mature B cells survive and start proliferation. In this study, we show that in Ch1 cell line which are a model system for immature mouse B cells, Surface IgM (sIgM) cross-linking leads to cell cycle arrest. we found that this immature B cells do enter, but fail to completely progress through G1 phase of the cell cycle following BCR engagement. Interestingly, IL-4, which by itself does not stimulate proliferation of immature B cells, could rescue these cells from G0 /G1 arrest. Consistent with this idea, IL-4 can reverse effect of anti-Ig Abs to promote cell cycle progression of immature B cells. To investigate the different signaling pathways involved in these processes, CH1 cells were stimulated with anti-IgM alone, with IL4 alone, or with a combination of both IL4 and anti-IgM. Following this western blot strategy, protein/DNA transcription factor arrays and microarray data were employed to monitor the evolution of the signaling cascades. we have analysed the role of the MAP kinase families (MAPK) cascades, which are required for growth-factor-stimulated replication and for differentiation of B cells. All the intermediate signal transducers and the distal transcription modulators were studied to understand how intracellular signals from these two distinct receptors integrate to make the conesquence cell-fate decision.
NOD1 Engagement Leads to Increased IL12/IL23 p40 and decreased IL-10 Expressions in Sarcoidosis as Compared to Healthy Subjects (98.17)
Authors: Samavati Lobelia , Du Wenjin , Rastogi Ruchi , Nuñez Gabriel 
Published: January 2023

Abstract
Sarcoidosis is a systemic inflammatory disorder of unknown etiology affecting barrier organs like lung and skin. The presence of granuloma and its associated inflammation may lead to organ dysfunction.
Two NLR family members, NOD1 and NOD2, trigger immune defenses in response to bacterial peptidoglycans (PGNs). Interaction between these sensors and microbial moieties leads to up-regulation of cytokines involved in innate and adaptive immunity. We hypothesize that granuloma formation in sarcoidosis is due to an abnormal sensing of specific microbial constituents through NOD1, leading to an aberrant induction of pro-inflammatory and/or a decreased anti-inflammatory cytokines.
Methods: We assessed the functional responses of whole blood or isolated PBMC of patients with established diagnosis of sarcoidosis in response to NOD1 and TLR agonists and compared to those of healthy subjects. Pro- and anti-inflammatory cytokines were measured at the gene and protein levels.
Our results demonstrate that subjects with sarcoidosis expressed several cytokines including IL-1β, IL-8 and IL-6 significantly higher at baseline as compared to healthy controls. Secondly we show for the first time that patients with sarcoidosis respond to NOD1 stimulation and to co-stimulation of NOD1 and TLR4 receptors with a significant increase of IL12/IL23 p40 and decrease of IL-10 expressions at both the gene and protein levels.
Expression and function of bovine CCL28 (98.28)
Authors: Wilson Eric , Distelhorst Kathryn , Hughes Mellissa , Griffith Shannon , Nygaard Tyler , Voyich Jovanka 
Published: January 2023

Abstract
Bovine mastitis represents the most costly disease of the dairy industry. In an effort to better understand natural host defense mechanisms against mastitis causing pathogens we have begun to characterize the bovine chemokine CCL28 (bCCL28). CCL28 is a dual function chemokine which has been shown to mediate migration of antibody secreting cells to mucosal tissues; this chemokine has also been shown to function as an antimicrobial protein. We have found that expression of bCCL28 mRNA in bovine mucosal tissues is highly variable with highest expression in exocrine glands, including mammary gland and milk. Additionally, we demonstrate that recombinant bCCL28 has antimicrobial activity against mastitis causing microorganisms, including Staphylococcus aureus, Streptococcus uberis, and Streptococcus agalactiae. These results demonstrate that bCCL28 is expressed in mucosal tissues and exhibits potent antimicrobial activity in vitro, suggesting that this dual function chemokine may serve an important role in bovine immunity.
OPN expression by epithelial tubular cells regulates NK cell-mediated kidney ischemia reperfusion injury (98.30)
Authors: Zhang Zhu-Xu , Shek Kelvin , Wang Shuang , Huang Xuyan , Yin Ziqin , Sun Hongtao , Liu Weihua , Garcia Bertha , Rittling Susan , Jevnikar Anthony 
Published: January 2023

Abstract
Renal ischemia reperfusion injury (IRI) is a major cause of acute injury in both native and transplanted kidneys. This type of kidney injury is considered an antigen-independent inflammatory condition that involves multiple factors leading to tubular and endothelial dysfunction. We have recently found that NK cells induce apoptosis in tubular epithelial cells (TEC) and contribute to renal IRI. Kidney can express osteopontin (OPN) during injury. Therefore we examined the role OPN in NK cell function and kidney IRI.
We have found that TEC expressed high levels of OPN in vitro and in vivo after injury. Kidneys in OPN-/- mice had less severity of IRI compared to wild-type mice (P&lt;0.05). Interestingly, recombinant OPN could activate NK cells that express high levels of perforin and granzyme and could mediate TEC apoptotic death. Importantly, we have found that NK cell migrate towards OPN protein as well as OPN-producing TEC in the transwell assay. Whereas, less NK cell migration was seen towards OPN-/- TEC (P&lt;0.01). Further more, Kidneys in OPN-/- mice had less NK cell infiltration after IRI compared to WT mice (P&lt;0.02). Taken together, our study results support a previously unrecognized role for TEC expression of OPN in NK cell-mediated kidney injury. TEC expression of OPN promotes early kidney inflammatory and IRI, and limiting OPN expression may improve kidney function and graft survival.
CXCL13-CXCR5 interactions support prostate cancer cell migration and invasion in a PI3K p110-, SRC- and FAK-dependent fashion (98.5)
Authors: El-Haibi Christelle P , Johnson Paul R , Sharma Praveen K , Suttles Jill , Singh Shailesh , Lillard, Jr. James W 
Published: January 2023

Abstract
We have previously shown that CXCR5 is significantly expressed by the prostate cancer (PCa) tissue than compared to high grade prostatic intraepithelial neoplasia and benign prostatic hyperplasia. We have also demonstrated PCa cell lines significantly express functional CXCR5, which promote cell invasion, migration, and active matrix metalloproteinase expression. In the present study, we elucidate the molecular mechanisms of PCa cell migration and invasion mediated by CXCL13-CXCR5. Using phospho-specific antibody microarray and Western blot analyses, we have delineated the pathways involved in CXCL13-CXCR5 signaling by PCa cell lines. For the first time, we show Gα, Gβ, and Gγ protein isoforms are differentially expressed by normal prostatic epithelial cell lines (PrEC and RWPE-1) versus PCa cell lines (PC3, DU145, LNCaP, and C4-2b). We also illustrate LNCaP cells express PI3K-p110α, -p110β, and -p110δ, while PC3 cells express PI3K-p110α, -p110β, -p110γ, and DOCK2. Migration and invasion assays revealed that both PC3 and LNCaP cell lines invade and migrate toward CXCL13 in a PI3K-dependent fashion. Src-FAK were required for this CXCL13-mediated migration and invasion. PC3 cells were capable of exploiting both PI3K-p110α/β /γ- and PI3K-p110γ-integrin β3-mediated events for migration and invasion, while LNCaP cells were only able to use PI3K-p110α/β /δ-dependent mechanisms for progression. In conclusion, the diversity of G protein and PI3K p110 isoforms along with Src- and FAK-signaling dictate the potential of PCa cell lines to migrate and invade in response to CXCL13.
Adipocyte culture medium increases metastasis of MDA-MB-231 cells through production of CCL20 (98.6)
Authors: Yang Young , Park Jeong-Su 
Published: January 2023

Abstract
We tried to identify chemokine that involved in communication between adipose tissues and breast cancers. In order to examine whether adipocyte culture medium (adipocyte-CM) affects the secreted chemokine profile of tumor cells, because adipocytes, as stromal cells, stimulate progression or metastasis of breast cancer cells, and chemokines secreted from tumor cells are involved in these processes, MDA-MB-231 cells were treated with adipocyte-CM and preadipocytes-CM. CCL20 expression was dramatically increased, and an NF-κB blocker completely inhibited adipocyte culture medium-induced CCL20 expression in MDA-MB-231 cells. We showed that adipocyte culture medium increased the production of TNF-α in MDA-MB-231 cells, which stimulated CCL20 expression in an autocrine fashion. Our data also showed that CCL20 increased the migration and invasiveness of MDA-MB-231 cells, but did not affect the proliferation of these cells. Adipocyte-CM stimulates migration and metastasis of breast cancer cells through the increase of CCL20 production, indicating that adipose tissue positively regulates microenvironment of breast tumours.
This work was supported by the Biogreen 21 project (20070301034031) of Rural Development Administration.
Dual role of CD8+ T cells in PLPp91-110 induced experimental autoimmune encephalomyelitis in HLA-DR3.Abo transgenic mice (99.1)
Authors: Mangalam Ashutosh K , Luckey David , Smart Michelle , Pease Larry , Rodriguez Moses , David Chella 
Published: January 2023

Abstract
MS is an inflammatory demyelinating disease of CNS with a presumed autoimmune origin. Prevalent data from animal model of disease, experimental autoimmune encephalomyelitis (EAE) suggests that myelin-specific CD4 T-cells play a major role in disease. Role of CD8 T-cells in MS/EAE has been enigmatic as it has been assigned either regulatory or pathogenic role in disease. Previously we have shown that PLPp91-110 peptide can induce inflammatory neurological disease in HLA-DR3 transgenic (Tg) mice. In order to understand the role of CD8 T cells in this humanized model, we generated HLA-DR3 Tg mice lacking CD8 T cells (DR3.CD8-/-). These mice showed earlier onset and more severe disease when compared to CD8 sufficient HLA-DR3 Tg mice indicating that CD8 T-cells plays a regulatory role. However, pathological analysis of DR3.CD8-/- mice with EAE showed less inflammation and demyelination in CNS compared to DR3.CD8 sufficient mice suggesting a second pathogenic role of CD8 T cells. Thus, our data suggests both a regulatory as well as a pathogenic role of CD8 T cells in EAE and possibly in MS. We have characterized both subsets in detail and show that CD8+CD122- T cells are regulatory subset of CD8 T cells and suppress CD4 T cells by inhibiting antigen presentation pathway, while CD8+CD122- T cells are pathogenic subset. Thus ours is the first study to show a dual role of CD8 T cells in the onset, incidence, progression, severity and pathogenesis of EAE/MS.
Characterizing the pathophysiology of Systemic Lupus Erythematosis disease progression in the BXSB Yaa CD8-/-, IL15 -/- mouse model (99.16)
Authors: McPhee Caroline , Bubier Jason , Morse Herbert , Foreman Oded , Roopenian Derry 
Published: January 2023

Abstract
Systemic Lupus Erythematosis (SLE) is a common autoimmune disease affecting mainly women and people of non Caucasian descent. This disease varies in severity and presentation but death due to renal failure is the most common outcome. The BXSB Yaa mouse has been a widely accepted model for the study of SLE. In an attempt to further illuminate the pathogenesis of this disease, CD8 and interleukin 15 were genetically removed from this model. The resulting congenic mouse develops an SLE like disease at an accelerated rate, succumbing to disease in half the time of the BXSB Yaa (3 months versus 6 months of age). Immunoglobulin levels are high at an early age in these mice. A loss of architecture and overwhelming plasmablast cell populations are seen histologically in the spleen and lymph nodes. These plasmablast cells were also found in the gastric mucosa, lung parenchyma, and renal tissues. Through immunoflorescence (IFA) and flow cytometry of splenic tissue, a number of these cells appear to be B220 negative and CD138 positive. There also appears to be an association with CD5, CD49b, and CD43. IFA has also revealed a loss of normal orientation between B220 labeled and CD4 labeled cells in the spleen and lymph nodes of these mice as well as many CD138 positive cells throughout these tissues. Further characterization of these cells is being pursued as well as age related studies in these mice to further define the pathogenesis of SLE.
Persistence of FOXP3 expression is impaired in RR-MS Tregs (99.3)
Authors: Schneider Anya , Long Sarah Alice , Kita Mariko , Buckner Jane H 
Published: January 2023

Abstract
Impaired Treg function may contribute to the development of Multiple Sclerosis (MS). FOXP3 is required for Treg function and its expression is maintained by the common γ-chain cytokines through phosphorylation of STAT5 (pSTAT5). We examined the pSTAT5 levels of CD4+CD25+Treg from relapsing remitting MS and control subjects in response to low-dose IL-2. We found that, despite equivalent levels of CD25, pSTAT5 was lower in RR-MS subjects (p= 0.0013), indicating a mechanism by which FOXP3 expression and Treg function may be lost in MS. To further examine the expression and persistence of FOXP3 in these subjects we generated adaptive Tregs and followed FOXP3 expression in these cells over time. We found that the initial induction of FOXP3 was similar to that of controls, but by day 10 of culture FOXP3 expression in CD4+CD25+ T cells was significantly lower (p&lt;0.0001). FOXP3 expression could not be rescued by IL-2, IL-7 or IL-2/IL-7 in combination. In addition, cell surface expression of CD122 and CD132 is significantly decreased on RR-MS CD4+ CD25+ T cells. Taken together we conclude that the impaired persistence of FOXP3 expression in aTreg may impact the number and function of Tregs in individuals with RR-MS. This loss of FOXP3 may be due to decreased pSTAT5 in response to IL-2 and IL-7 which may be due to decreased levels of the IL-2R and IL-7R complexes. This work was supported by grants from the JDRF33-2008-398 and DFG108312-1.