bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the role of interferon-alpha in Sjögren’s Disease (101.36)
Authors: Shen Long , Wu Jing , Suresh Lakshmanan , Ambrus, Jr. Julian 
Published: January 2023

Abstract
We have previously demonstrated that IL14a transgenic mice (IL14aTG) reproduce features of Sjögren’s disease (SD) seen in patients in the same relative time frame, including autoantibodies, early destruction of the salivary and lachrymal glands, infiltration of the salivary and lachrymal glands with lymphocytes, lymphocytic pneumonia, mild renal disease and eventually lymphoma (J.Immunol. 177: 5676, 2006 and Clin. Immunol. 130:304, 2009). We have more recently demonstrated that lymphotoxin is an important early mediator of salivary gland injury in IL14aTG mice and patients with SD (J.Immunol. 185: 6355, 2010). In our current studies we investigate the role of interferon-alpha (IFN-α) in SD in IL14aTG mice. We demonstrate that IL14aTG mice lacking the type I IFN receptor (IL14aTG.IFNa/bR-/-) have the same early injury to the submandibular glands as IL14aTG mice. However, IL14aTG.IFNa/bR-/- do not get the later parotid gland injury that is seen in IL14aTG mice. Both IL14aTG mice and IL14aTG.IFNa/bR-/- get lung injury, but IL14aTG mice get a lymphocytic pneumonia and IL14aTG.IFNa/bR-/- get a mild perivascular and peribronchial lymphocytic infiltration. Thus, IFN-α is not critical in early stages of SD but involved in disease manifestations that occur after original salivary gland injury. These data have important implications for the use of IFN-α inhibitors in the treatment of SD.
Analysis of Type I and III interferon levels in the sera of normal and autoimmune donors. (101.37)
Authors: Lavoie Thomas , Pandya Yognandan , Skawinski Michael , Crisafulli-Cabatu Sara , Moolchan Karlene , Stauffer Tara 
Published: January 2023

Abstract
We have begun examining serum levels of Type I and III interferons in normal and autoimmune donors by ELISA and a Type I reporter gene activity assay to determine if there are expression pattern signatures of these diseases. Samples were obtained from normal donors and patients with Systemic Lupus Erythematosus, Rheumatoid Arthritis or Multiple Sclerosis and assayed for IFN-α), IFN-β, IFN-ω, and IFN. Normal controls had little detectable IFN-α, IFN-ω, or Type I IFN activity. Low levels of IFN-β were detected in 15% of the normal controls. Approximately 35% of the normal controls had detectable IFN-λ. In the Lupus samples, 45% had detectable IFN-α. IFN-ω and IFN-β were detected in 20 and 40%, respectively, of the Lupus samples. Overall, greater than 80% of the Lupus samples had detectable Type-I IFN. Rheumatoid arthritis samples may have elevated IFN-β and IFN-ω relative to normal controls, but not IFN-α. Multiples sclerosis samples had a slight tendency towards elevated IFN-β. A low percentage of Lupus and multiple sclerosis samples had detectable Type-I IFN activity by the reporter gene assay. None of the samples displayed significant differences in Type III IFN expression. Multiplex ELISA was used to examine a subset of the samples for cytokine profiles and in Lupus samples IL-13 was decreased. In arthritis samples IL-8 and IL-23 were elevated, while in Multiple Sclerosis samples IL-2, IL-4 and IL-10 were elevated. The implications of these results will be discussed.
Galectins flip the CD40 survival-and-proliferation switch off and on in autoimmunity. (101.39)
Authors: Vaitaitis Gisela , Wagner David 
Published: January 2023

Abstract
CD40 is intimately associated with autoimmune disease. CD4+CD40+ T cells (Th40) are necessary and sufficient in transferring autoimmunity and CD40 engagement induces survival and proliferation of those cells. Several CD40 receptor constellations exist being composed of different glycoforms of CD40 and some are hybrid receptors with TNFR1 and 2. Autoimmune and non-autoimmune mouse Th40 cells differ in their CD40 glycosylation status. Here we reveal that in-vivo CD40 signals to non-autoimmune BALB/c mice access glycosylation processes and induce a reduction in glycan branching to levels seen in autoimmune strains. Such levels are known to activate T cells. CD40 signals induce a less glycosylated form of CD40 itself. We reveal an interaction of galectins 3 and 9 with CD40 in Th40 cells that differs between autoimmune and non-autoimmune conditions. Those galectins counteract each other in controlling CD40 receptor signals. Galectin-3 interaction is associated with CD40 signals leading to survival/proliferation of autoimmune NOD Th40 cells. However, the addition of galectin 9 counteracts that interaction to promote CD40 interaction with galectin-9 which thwarts the survival and proliferation signals. Therefore we suggest that CD40’s impact on glycosylation events may have far reaching consequences for immune effector molecules beyond CD40 itself and that galectins 3 and 9 are controlling a “switch” that determines whether CD40 signals lead to survival and proliferation.
FTY720 increases the ratio of Treg:CD4 T cells in vivo and inhibits the development of autoimmune arthritis. (101.9)
Authors: Rosloniec Edward , Whittington Karen , Brand David , Hasty Karen , Miller David 
Published: January 2023

Abstract
Treg cells play an integral role in preventing autoimmunity, and the enhancement of Treg function is an attractive approach for the treatment of autoimmunity. Toward this goal, we have investigated the efficacy and mechanism of action of FTY720 in preventing autoimmune arthritis elicited by immunization of humanized mice with type II collagen. Mice were treated on the day of immunization with 1 or 0.2 mg/kg ip of FTY720, 3 times/wk for 3 wks, and evaluated for incidence and severity of arthritis and the phenotype of their T cell responses. Both 1 and 0.2 mg/kg of FTY720 significantly delayed disease onset (day 35 vs 22) and reduced the incidence and severity in comparison to vehicle control groups. By day 18, the percentage of B cells in the lymph nodes of the FTY720 treated mice had increased and CD4 T cells had decreased. Foxp3+ cells were also significantly increased in the nodes of the FTY720 treated group, to &gt;20%, more than 2 fold higher than the control group. This increase occurred in both the CD25hi and the CD25lo/neg Foxp3+ T cells. The increased number of Treg cells did not cause a reduction of autoimmune T cells as, based on tetramer analyses, the percent of CII-specific T cells in the lymph nodes were elevated 40% over the control group. These data indicate that the FTY720 did not interfere with the development of the autoimmune T cells response and that at least one mechanism of disease inhibition may be Treg cell inactivation of the autoimmune T cells.
Lung memory CD4 T cell subsets with different tissue retentive properties (102.1)
Authors: Turner Damian , Teijaro John , Yudanin Naomi 
Published: January 2023

Abstract
Memory T cells residing in the lung can mediate protective immunity to pathogens; however, the mechanism of lung cell recruitment and retention is unknown. We have shown that antigen-specific lung memory CD4 T cells can traffic to the lung and become irreversibly retained there, whereas lymphoid memory T cells distribute widely and are not retained in tissues. However, endogenous polyclonal lung memory CD4 cells migrate to the lung and additional tissue sites. We hypothesized that the lung memory CD4 T cell population is comprised of both tissue-resident and circulating subsets. To identify these subsets we labeled CD4 cells by intravenous administration of fluorescently labeled anti-CD4 antibody and found that 25% of CD4 cells in lungs were protected from labeling and were mostly CD11ahi CD69+. Inhibiting lymphocyte circulation with FTY720 resulted in a decrease in lung naïve cells but retention of the memory cells enriched for CD11ahi CD69+ cells. We have also found that tissue-specific recruitment of lung memory cells was inhibited by pertussis toxin, suggesting the involvement of chemokine receptors. Microarray and phenotypic analysis revealed higher expression of CCR6 and CD103 by lung memory CD4 cells. Transfer of lung memory CD4 cells resulted in CCR6+ and CD103+ donor cells being enriched in the lung-recruited population. Our data suggest that the lung memory CD4 T cell population consists of a circulatory subset and a tissue-retentive subset with distinct phenotypes.
Computer simulation of lymphocyte traffic through the homeostatic lymph node (102.14)
Authors: Billard Matthew , Kepler Thomas 
Published: January 2023

Abstract
Lymphocytes recognize their rare cognate antigens within the complex microenvironment of secondary lymphoid organs (SLO). Proper lymphocyte migration into, through, and out of SLO is essential to immune system function and is regulated via chemotactic signals transduced through a well-known set of receptors. Specifically, CCR7, CXCR5, and S1P1 are critical lymphocyte receptors with varied expression and function depending on the lymphocyte cell type, activation state, or differentiated subtype. Our group created a flexible, modular, 3D simulation environment to investigate chemokine control of lymphocyte traffic through SLO. Simulations using computational modeling compliment and drive experimental research by performing in silico experiments that can predict outcomes and inspire new hypotheses. In our system, lymphocyte behavior is principally controlled by two models, a Langevin motility model and a chemokine receptor dynamics model. Using this simulation software, we have asked questions pertaining to the basic cell biology of lymphocytes in order to better understand the mechanisms these cells use to initiate and coordinate inflammatory responses to pathogens. This robust software platform is designed for future modification and expansion, allowing the user to replicate published data, fit models, design in silico experiments, and test new hypotheses.
Podoplanin-rich stromal networks induce dendritic cell motility via activation of CLEC-2 (102.21)
Authors: Pinner Sophie , Turley Shannon 
Published: January 2023

Abstract
Cell motility is crucial for leukocytes to traffic between tissues and to interact with one another and their microenvironment. Stromal cells provide 3-dimensional scaffolds and molecular cues that coordinate leukocyte migration and compartmentalization within secondary lymphoid organs. Dendritic cells (DCs) are antigen presenting cells whose migration via stromal networks is critical for the induction of both immunogenic and tolerogenic T cell responses. DCs migrate in an amoeboid, integrin-independent manner, utilizing the chemokine receptor CCR7 to navigate their way to lymph nodes (LNs). However the molecules utilised by DCs and other leukocytes to interact with stroma are still largely unknown. Here we describe a novel motility mechanism driven by the glycoprotein podoplanin (gp38) that induces motility of DCs that express the C-type lectin-like receptor 2 (CLEC-2, CLEC-1b). Podoplanin-mediated activation of CLEC-2 promotes dynamic, actin-rich protrusions, and migration along stroma. The podoplanin-CLEC-2 interaction endows DCs with the capacity to crawl along stromal cell scaffolds of secondary lymphoid organs and to find and properly activate T cells. Our results illuminate a novel mechanism of leukocyte migration pertaining to multiple steps in the adaptive immune response which we propose functions in concert with chemokine gradients to ensure efficient, directional leukocyte trafficking.
Effects of aging on vaccine efficacy in nonhuman primate models (104.1)
Authors: Arteaga-Cortes Lourdes , Pasquali Amanda , Blevins Maria , Jorgensen Matthew , Leland Michelle , Kaplan Jay , Rice Karen , Dube Peter , Stacy Sue , High Kevin , Kraig Ellen 
Published: January 2023

Abstract
Vaccines are frequently less efficacious in the elderly and correlates of protection in older adults often differ from those seen in younger individuals. However, clinical testing of new vaccine formulations is typically limited and does not include elderly subjects. In order to identify a nonhuman primate (NHP) model that would recapitulate the effects of immunosenescence in humans, we assessed immune responses in three different NHPs: baboons (Papio), rhesus macaques (Macaca), and African green monkeys (Chlorocebus). The F1-antigen, a capsular protein encoded on the plague bacterium Y. pestis pFra plasmid, was chosen because it should elicit naive responses in all subjects. The animals were bled following primary and booster immunizations; B cell (antibody titer) and T cell parameters were assessed. As in humans, significant heterogeneity between individuals was seen. In rhesus and vervets, T cell responses to F1 were generally lower with increasing age. However, less of an age effect was observed in the baboons; this is consistent with the finding that antibody titers to F1 were not significantly diminished in older baboons and with our previous work showing immunization of old baboons with Y. pestis LcrV elicited high titer protective antibodies [JI 181:109]. Flow cytometric analyses of the T cell populations in old and young NHPs reveal differences across the species and provide additional insight into the immune parameters that correlate with healthy aging.
Elevated IL-7 availability does not account for T cell proliferation in moderate lymphopenia. (104.11)
Authors: Abraham Ninan , Patton Daniel , Seo Jung Hee , Osborne Lisa 
Published: January 2023

Abstract
Lymphopenia-induced proliferation (LIP) is a proliferative program initiated in response to T cell insufficiency caused by acute or chronic immunodepletion. Studies of lymphopenic mice have demonstrated that the cytokine IL-7 and TCR signaling are critical for LIP. We examined how these two factors impact T cell proliferation following transfer into moderately lymphopenic mice. We show here that moderate lymphopenia (~25% of WT lymphocytes) of IL-7Rα knock-in mutant (IL-7Rα449F) mice supports T cell proliferation, although with decreased frequency and kinetics compared to cells transferred to severely lymphopenic (5% of WT) IL-7Rα-/- hosts. Although previous studies have demonstrated that elevated IL-7 levels play an important role in LIP, IL-7 availability was not elevated in IL-7Rα449F mice. However, moderate lymphopenia increased access of transferred T cells to self-peptide presented on antigen presenting cells that can trigger TCR signaling and proliferation. Importantly, we did not detect significant changes in TCR Vβ usage of proliferated T cells recovered from either moderately or severely lymphopenic hosts. Our work demonstrates that polyclonal T cells retain a diverse TCR repertoire following proliferation mediated by either self-peptide/MHC interaction alone or in combination with IL-7, and that T cell reconstitution is most efficient in the presence of increased IL-7 availability.
Lasting alterations induced in murine skin T cell populations by chronic ethanol (EtOH) feeding (104.12)
Authors: Parlet Corey , Cook Robert , Coleman Ruth , Schlueter Annette 
Published: January 2023

Abstract
EtOH induced epithelial dysfunction is made evident by the diminished ability of alcoholics to fight skin infection and heal wounds; however the precise lesions responsible for these changes require clarification. Acute EtOH exposure in a rodent model induces alterations in inflammation and innate immunity detrimental to both host defense and wound healing responses in the skin. In addition, the skin is home to numerous immune cell populations including dendritic cells (DCs) and T cells. Using a murine model of chronic alcoholism, we previously reported that EtOH feeding imposes both numeric and functional defects upon skin DCs. There are currently no reports of how skin T cells are affected by chronic EtOH feeding. The present study used flow cytometry to evaluate the effect of chronic EtOH feeding on skin T cell numbers. EtOH feeding decreased the number of epidermal and dermal T cells expressing the γδ T cell receptor. These numeric alterations persisted five weeks after EtOH withdrawal. Given the established roles for γδ T cells in innate immunity and tissue repair, their deficiency in EtOH fed mice may help explain why alcoholism is associated with both impaired skin immunity and wound healing. Experiments are underway to investigate alterations in the number of skin regulatory T cells, further define the mechanism(s) for numeric changes, and potential functional alterations of skin T cells due to EtOH feeding.
BCL-2 allows effector and memory CD8+ T cells to tolerate higher expression of BIM (104.19)
Authors: Kurtulus Sema , Tripathi Pulak , Moreno-Fernandez Maria , Sholl Allyson , Katz Jonathan , Grimes Harry , Hildeman David 
Published: January 2023

Abstract
As acute infections resolve, most effector CD8+ T cells die, while some persist and become memory T cells. Recent work showed that subsets of effector CD8+ T cells, identified by reciprocal expression of KLRG1 and CD127, have different lifespans. Similar to previous reports, we found that effector CD8+ T cells reported to have a longer lifespan (i.e. KLRG1lo CD127hi) have increased levels of Bcl-2 compared to their shorter lived KLRG1hi CD127lo counterparts. Surprisingly, we found that these effector KLRG1lo CD127hi CD8+ T cells also had increased levels of Bim compared to KLRG1hi CD127lo cells. Similarly, central memory CD8+ T cells (TCM) expressed higher levels of Bim and Bcl-2 than did effector memory CD8+ T cells (TEM). Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8+ T cells required Bcl-2 to combat the pro-apoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8+ T cells. Finally, we found that Bim levels were significantly increased in effector CD8+ T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate.
Changing access to STAT proteins in CD8 T cells responding to lymphocytic choriomeningitis virus infection (105.31)
Authors: Kallal Lara , Kim Kwang-Sin , Biron Christine 
Published: January 2023

Abstract
Signal transducer and activator of transcription (STAT) proteins are a family of transcription factors that can be activated by particular cytokines regulating immune responses. Previous work in our laboratory has shown that STAT protein levels are dynamically regulated in cells, and this influences cytokine access to particular STATs with subsequent functional outcome. Herein, we examined STAT3 and STAT4 levels as well as cytokine activation of these STATs in CD8 T cells responding to infection with lymphocytic choriomeningitis virus (LCMV). The type I interferon (IFN), IFN-alpha, and IL-12 activated high phosphorylated (p)STAT4 levels in CD8 T cells only at late (day 8) timepoints following LCMV infection, whereas IL-6 and IL-21 activated high pSTAT3 levels only at early (day 2) and intermediate (day 5/6) timepoints after LCMV infection. Western blot analyses indicated that compared to day 0, STAT4 levels in CD8 T cells were highly increased at days 5 and 8, whereas STAT3 levels were decreasing at day 5 and very low at day 8. Assessment of T cell proliferation by BrdU incorporation showed that proportional to CD8 T cell numbers, the highest proliferation of cells occurred at day 5/6. Taken together, these studies suggest a key switch in STAT access from STAT3 to STAT4 in CD8 T cells responding to LCMV infection, which may correlate with the functional status of CD8 T cells.
Assessment of the role of CD4 and CD2 in plasmacytoid dendritic cells in response to HIV infection. (105.32)
Authors: Mwangi David , Fitzgerald-Bocarsly Patricia 
Published: January 2023

Abstract
pDC secrete type 1 interferons and pro-inflammatory cytokines upon viral stimulation through either TLR7 or TLR9. The numbers and function of pDC are impaired in HIV infection, but the mechanism of this deficiency is not fully understood. pDC express CD4, CXCR4 and CCR5, which serve as receptor and co-receptors for the HIV viral envelope protein, gp120. A subset of pDC also expresses CD2. The functional significance of these molecules on pDC in HIV infection is unknown. We hypothesize that CD4 is involved in DC:DC and/or TC:DC communication that leads to modulation of pDC function and that CD2 may augment the structural integrity of the virological or immunological synapse. Our data demonstrate that CD4 cross-linking inhibits activation of pDC as evidenced by a decrease in HSV-1-induced CD40 and HLA-DR and IFN-a production, and inhibits translocation of NF-kB to the nucleus. We compared TLR and NF-kB expression in the CD2+ and CD2- pDC subsets. Our preliminary data shows that CD2+ pDC expressed higher levels of TLR9 and TLR7 than that of CD2- pDC, while the CD2- subset shows higher levels of NF-kB. Neither IFN-a nor TNF-a production was different between CD2+ and CD2- subsets when stimulated with HIV-1. Interestingly, the CD2+ expressed higher levels of the HIV co-receptor, CXCR4, but not CCR5 than the CD2- subset. Future studies will seek to understand the significance of these findings with respect to activation of pDC and their potential interactions with HIV-1.
Exogenous and endogenous virus interactions in head and neck cancer immunity (105.34)
Authors: Sutkowski Natalie , Hoel Brian , Gibbs Kevin , Sun Wei , Halstead Lucinda , Huber Brigitte , Garrett-Mayer Elizabeth , Hill Elizabeth , Gillespie M. , Rubinchik Semyon 
Published: January 2023

Abstract
We report that two common tumor viruses etiologically associated with head and neck cancer, Epstein-Barr virus (EBV) with undifferentiated nasopharyngeal carcinoma, and human papillomavirus (HPV) with oropharyngeal squamous cell carcinoma, transactivate an endogenous retrovirus (HERV-K18), which encodes a superantigen that activates TCRBV13 T cells. EBV LMP-2 transactivated the HERV-K18 superantigen in nasopharyngeal epithelial cells, and EBV-associated nasopharyngeal carcinomas expressed the superantigen. HPV type-16 E6 and E7 proteins also transactivated the HERV-K18 superantigen in oropharyngeal epithelial cells, and superantigen expression was significantly increased in HPV16-associated carcinomas. Serum cytokine levels in head and neck carcinoma patients indicated that there were distinct inflammatory profiles associated with exogenous and endogenous viruses. HPV-associated patients had increased levels of serum IL-8, while HPV-negative patients had higher serum IL-6 and G-CSF levels. Interestingly, HERV-K18 superantigen levels correlated independently with serum levels of the Th2 cytokine IL-13. Among HPV+ tumors, gene expression array analyses indicated that B cell specific genes were significantly upregulated in the superantigen high group. Our results suggest that endogenous superantigen expression in HPV+ tumors was associated with a Th2 immune response, demonstrating that chronic and endogenous viruses comprising the virome affect both host and tumor immunity.