bluuebunny/crossref_metadata_2025_split huggingface dataset:
The alternative NF-kappa B pathway is essential for OX40-induced CD4 T cell differentiation and effector function (47.19)
Authors: Murray Susan E. , Rowe Alexander M. , Basak Soumen , Hoffmann Alexander , Parker David C. 
Published: January 2023

Abstract
Nuclear factor-kappa B (NF-κB) is an evolutionarily conserved signaling pathway that alerts the immune system to infection and danger. NF-κB can be divided broadly into two pathways-the canonical pathway regulated by IκB and the alternative pathway that depends on NF-κB inducing kinase (NIK) and IKKα. Mediators as divergent as pathogen-associated antigens, reactive oxygen species, UV light, and cytokines can activate the canonical NF-κB pathway. Activation of the alternative pathway seems to be limited to a subset of TNFRs, the best studied of which are LTβR, BAFFR, and CD40. Mice with lesions in the alternative NF-κB pathway have disorganized lymphoid structures and few peripheral B cells, but T cell responses in these mice have been less well-studied. Here, we show that the costimulatory TNFR, OX40 (CD134), activates the alternative NF-κB pathway in primary CD4 T cells. Activation of the alternative NF-κB pathway is necessary for OX40-induced differentiation and acquisition of effector function in vivo. Moreover, inability to activate the alternative NF-κB pathway rendered T cells unable to induce lethal GVHD. These results demonstrate a critical role for the alternative NF-κB pathway in CD4 T cell responses, and suggest that interventions targeting this pathway may have therapeutic potential.
Supported by NIH R21 AI077032 (D.C.P.) and NIH T32 HL007781 (S.E.M.)
Prevalence of NK-like T cells and plasma Th1/Th2 cytokines, but not CMV seropositivity, correspond with health and performance of older adults (47.2)
Authors: Hamel David L , Mueller Robert G , Michel Joshua J , Boudreau Robert , Newman Anne B , Vallejo Abbe N 
Published: January 2023

Abstract
We have reported the accumulation of NK-like T cells with aging. Others reported associations between ill-health and certain cytokines or anti-viral serology. Here, we examined whether health of older adults could be defined by immunologic signatures. Survivors of a long term epidemiological study of aging who had been monitored in the last 20 years (n=140, aged =85 yrs) were recruited, and clinically tested for physical and cognitive performance. Blood samples were examined for T cell phenotypes, and 24 humoral factors including antibodies to CMV, EBV, and VZV. Clinical tests showed 59% of subjects were fully functional, and 41% had physical/cognitive impairments. All subjects had generalized upregulation of cytokines and anti-viral antibodies; but only T cells and cytokines showed significant Spearman correlations (P&lt;0.01). Normalized factor analysis showed distinct immunological profiles between the two groups. The impaired group had TNFα/IL6 cytokine signature, and a cell signature of T cells expressing CD158A/E. In contrast, the functional group had a humoral signature dominated by IFNγ, IL4, IL5, and IL13, and a cell signature of T cells expressing CD56; intact function predicted by IFNγ and IL5 (P&lt;0.05) in logistic models. These data indicate distinct immune physiology of older adults; CD56+ T cells within a Th1-Th2 cytokine environment are likely effectors of favorable health outcomes with aging.
Critical role for the transcription factor T-bet in regulating the development of Th17 responses during parasitic infection (47.20)
Authors: Smeltz Ronald , Guo Siqi , Cobb Dustin 
Published: January 2023

Abstract
CD4+ Th17 cells have emerged as a new T cell subset in the Th1/Th2 paradigm, and efforts have shifted toward understanding the factors that regulate their development in vivo. To analyze the role of the transcription factor T-bet in regulation of Th17 cells, we utilized a murine model of Trypanosoma cruzi infection, an intracellular pathogen that causes Chagas disease in humans. Infection of t-bet-/- mice led to normal, unimpaired development of antigen-specific CD4+ T cells producing IFN-g. However, a robust Th17 response developed concomitant with Th1 responses. Despite significant IFN-g production, the physiological effects of IL-17 prevailed as there was a sharp increase in Gr-1+Ly6G+ neutrophils. Adoptive transfer of T cells from infected t-bet-/- mice into rag-2-/- mice (t-bet+/+) revealed that CD4+ T cells maintained their IL-17-producing phenotype, including those cells capable of producing both IFN-g; and IL-17. Furthermore, and in contrast to the effects of IL-2 on Th17 development, IL-2 had no effect on IL-17 production by primed T cells. Importantly, adoptive transfer of T cells from naive t-bet-/- mice into infected rag-2-/- mice recapitulated the differentiation of T. cruzi-specific Th17 cells observed in infected t-bet-/- mice. Conversely, transfer of wild-type T cells into infected t-bet-/- mice did not reveal an increase in Th17 development. These results demonstrate that T-bet regulates the differentiation of T. cruzi-specific Th17 cells in vivo in a T cell-intrinsic manner. These data provide important insight into the role of T-bet in regulation of parasite-specific Th17 responses.
Role of Interleukin-27 in a vaccination model against Mycobacterium tuberculosis (MTb) (47.25)
Authors: Torrado Egidio , Fountain Jeffrey J. , Martino Cynthia A. , Khader Shabaana A. , Cooper Andrea M. 
Published: January 2023

Abstract
Previous work from our laboratory has shown that vaccination with an I-Ab restricted peptide of an MTb antigen emulsified in Monophosphoryl lipid A/Trehalose dimycolate (MPL/TDM) and Dimethyl dioctadecylammonium bromide (DDA) confers specific protection following an aerosol infection with MTb. This protection is mediated through IL-17+ cells that colonize the lung and recruit protective Th1 cells. Although there is a current appreciation of the pro- and anti-inflammatory properties of IL-27 in different models of inflammation, the role of this cytokine in vaccination models is poorly understood. Since IL-17+ cells are regulated by IL-27, we wanted to clarify the role of IL-27 in our vaccination model. Immunization of mice with MPL/TDM+peptide leads to the development of IFNγ+ cells. On the other hand, DDA is required for the development of IL-17+ cells by inducing expression of TGFβ and IL-6. Although the IFNγ response is similar in WT and IL-27R KO, the latter show a higher frequency of IL-17+ cells both in the draining lymph nodes and lung, even in the absence of infection. Mechanistic analysis of the impact of IL-27 in effector generation after vaccination suggests differences in cell survival and polarization between IL-27R sufficient cells activated in the presence or absence of IL-27R. These data suggest that IL-27 plays a role in the generation of effectors during vaccination.
This work was supported by NHI grant AI069121
PLZF controls the development of innate T cell effector functions. (47.28)
Authors: Sant'Angelo Derek B. 
Published: January 2023

Abstract
Invariant natural killer T cell (iNKT cells) have an innate immunity-like rapidity of response and the capacity to modulate effector functions of other cells. We show that iNKT cells specifically express the BTB-ZF transcriptional regulator PLZF. In the absence of PLZF, iNKT cells developed, but lacked many innate T cell features. PLZF-deficient iNKT cells accumulated in lymph nodes rather than in the liver, did not express NK markers and displayed a non-activated phenotype. PLZF-deficient iNKT cells failed to secrete high amounts of IL-4 and interferon-γ upon activation; however, some cells produced either IL-4 or IFN-γ, but not both. Finally, forced expression of PLZF in conventional CD4 and CD8 T cells results in these cells spontaneously acquiring memory/effector functions. PLZF, therefore, is the determinant of innate T cell effector functions.
Differential modulation of regulatory T cell activities by nonylphenol, octylphenol and diethylstilbestrol (47.3)
Authors: Jung Mi Young , Kim Tae Sung 
Published: January 2023

Abstract
Endocrine disrupters (EDs) are universally present in the environment and may influence health of wildlife and human. These include plastics, detergents, pesticides, industrial chemicals, phytoestrogen and synthetic estrogen for medical purposes. Although biological effects of EDs have largely focused on reproductive tissues, studies on immune system are relatively lacking. Recent cohort studies have showed that individuals and their offspring exposed to EDs had multiple immune disorders, including autoimmune diseases, SLE, and allergic diseases. The fact that EDs modulated interleukin-4 production, Th1/Th2 balance and IgE production suggests their potential effect on allergic immune responses. Regulatory T cells (Tregs) play pivotal role in maintaining immunological unresponsiveness to self-antigens and suppressing excessive immune responses deleterious to the host. Whereas Tregs in normal conditions regulate ongoing immune responses and prevent autoimmunity, imbalanced function or number of Tregs might perturb the immune homeostasis.
In this study, we investigated the effect of various types of EDs on proliferation, differentiation and functional activities of Tregs in vitro. EDs differentially regulated the functions of Tregs. Nonylphenol and octylphenol increased CD4+CD25+Foxp3+ T cell population when combined with TGF-β. Diethylstilbestrol significantly inhibited the TGF-β-induced Treg differentiation and Foxp3 expression. In addition, DES recovered Treg-mediated suppression of CD4+ T cell proliferation, whereas the others had slight or no effects on the differentiation of Tregs. Several EDs like nonylphenol, octylphenol, bisphenol A increased proliferation of activated T cells. These results suggest that endocrine disruptors may modulate inflammation and cancer via Treg cells.
IL-25 promotes TH2 responses through the induction of IL-2 (47.34)
Authors: Zaph Colby , Artis David 
Published: January 2023

Abstract
Dysregulated CD4+ T helper type 2 (TH2) responses are a predominant feature of allergic inflammation, asthma and ulcerative colitis. Unlike TH1 and TH17 cells that employ distinct innate cell-derived cytokines to initiate their differentiation programs (IL-12 for TH1 cells and IL-6 and TGF-β for TH17 cells), TH2 cell development appears to be regulated primarily by autocrine IL-2 and IL-4. However, the factors that regulate expression of IL-2 in developing TH2 cells remain unclear. Here, we demonstrate that the cytokine IL-25 (IL-17E) induces early expression of IL-2 in developing TH2 cells, enhances TH2 cell proliferation and can promote TH2 cell development in the absence of IL-4Rα signaling. Surprisingly, IL-2 was not required for the IL-25-induced increase in CD4+ T cell proliferation, but the ability of IL-25 to promote TH2 responses was lost in the absence of IL-2. In vivo, treatment of resistant mice with an antibody against IL-2 results in impaired TH2 cell-mediated immunity to Trichuris infection. Together, these results identify IL-25 as an upstream differentiation factor for TH2 cells and suggest that manipulation of IL-25 may provide therapeutic benefits for diseases associated with dysregulated TH2 responses.
The effects of Aryl Hydrocarbon Receptor activation by TCDD on IL-12R signaling and generation of regulatory T cells (47.9)
Authors: Marshall Nikki B , Kerkvliet Nancy I 
Published: January 2023

Abstract
We have previously shown that allo-reactive donor CD4+ T cells are converted into CD25High Foxp3-negative regulatory T cells during an acute Graft-vs-Host Response (aGVHR) in mice treated with 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). Activation of the Aryl Hydrocarbon Receptor (AhR) in donor CD4+ T cells is required for full suppression of aGVHR and generation of regulatory T cells. CD4+ T cells exposed to TCDD during aGVHR exhibit a significant increase in IL-12Rb2 mRNA and protein as well as phosphorylated-STAT4 expression. We used IL-12Rb2-deficient (KO) donor T cells to determine whether increased IL-12R signaling was important for the generation of TCDD-induced regulatory T cells. CD25 protein expression was not changed on IL-12Rb2 KO cells compared to wild-type control (WT), however significantly fewer IL-12Rb2 KO T cells expressed phosphorylated-STAT4. A marked decrease in expression levels of phosphorylated-STAT1 and STAT5 was also observed in both WT and IL-12Rb2 KO donor T cells from TCDD-treated mice compared to vehicle control. Although IL-12Rb2 deficiency does not appear to affect the generation of donor-derived CD25High Foxp3-negative regulatory T cells during aGVHR in TCDD-treated mice, current studies focus on the effects of TCDD and altered IL-12R signaling on Foxp3-positive regulatory T cell generation.
Roles for Id3 in T Cell Development and Autoimmunity (48.17)
Authors: Mahlios Josh M , Zhuang Yuan 
Published: January 2023

Abstract
T cell development is a tightly regulated process that requires a number of known transcription factors, one of which is Inhibitor of Differentiation 3 (Id3). Here we find that Id3 plays an important role during thymopoiesis by preventing the development of an autoimmune condition similar to that of primary Sjogren's Syndrome. In the absence of a functional Id3 protein, thymocyte development is dysregulated and leads to the production of T cells capable of inducing symptoms associated with Sjogren's Syndrome. The T cell repertoire is altered in a manner in which large numbers of γδ T cells are produced, raising the question as to which subset(s) of T cells might be responsible for the induction of autoimmunity. Through the use of various genetic knockout mouse models, we have identified αβ rather than γδ T cells as an important population required for many of the phenotypic abnormalities associated with Sjogren's Syndrome.
IL-6 may interfere with the development of functional adaptive Tregs in NOD mice (48.19)
Authors: Azeem Nabeel , Triplett Ashley S , Parnell Sarah , Zhao Yuan , Alard Pascale , Kosiewicz Michele M 
Published: January 2023

Abstract
The cytokine milieu dictates whether TGF-β induces naïve CD4 cells to become adaptive regulatory cells or pro-inflammatory Th17 cells. We have found previously that while NOD CD4+CD25- cells convert into CD4+CD25+Foxp3+ cells in vivo, these cells are unable to regulate. The conversion defect in NOD mice appears to reside in the APC, and not the T cell, compartment, and transfer of B6.g7 or Idd3/5 DCs can reconstitute effective conversion in NOD mice. We report here preliminary results indicating that NOD DCs cultured with BDC2.5 CD4+CD25- cells, antigen and varying doses of TGF-β are less effective mediators of conversion into Foxp3+CD4+ cells than B6.g7 or Idd3/5 DCs. Furthermore, NOD DCs produce more IL-6 than either B6.g7 or Idd3/5 DCs both constitutively and after LPS stimulation in vitro. Interestingly, spleen and LNs (including pancreatic) from NOD mice contain higher (albeit small) numbers of IL-17+CD4+ cells than control mice. Taken together, these data could indicate that IL-6 produced by APC in NOD mice may interfere with the conversion of naïve CD4+ cells into functional adaptive regulatory T cells by driving these cells toward an Th17-like pathway. Funded by NIH R01 AI064421.
Cyclosporine A and CTLA-4Ig differentially inhibit the effector phase of the DTH response in two separate mouse strains (48.20)
Authors: MacLeod Heather , Goodwin Debbie , Damphousse Christy , Nickerson-Nutter Cheryl 
Published: January 2023

Abstract
Delayed type hypersensitivity (DTH) is classically defined as inflammation involving antigen presentation, cytokine production and T cell activation. Both the Balb/c strain and the autoimmune-prone B6D2F1 strain develop a DTH response. However, DTH in the Balb/c strain is inhibited by the immunosuppressive agent cyclosporine A (CsA), which blocks NFAT activity, whereas DTH in the B6D2F1 strain is not. Balb/c mice generate a traditional Th1 cytokine response that is inhibited by CsA, while B6D2F1 mice produce lower levels of Th1 cytokines and not all are reduced by CsA. Since T cell activation can also occur by costimulation through CD28, we hypothesized that the B6D2F1 DTH effector response may involve activation through CD28 that is not affected by CsA. To test this hypothesis, CTLA-4Ig, which blocks CD28, was administered with and without CsA at the effector phase. Our data indicate that to inhibit DTH in the B6D2F1 strain, both CD28 and NFAT activity must be simultaneously blocked, since neither CsA nor CTLA-4Ig alone were effective. In contrast, CsA is sufficient to block DTH in Balb/c mice indicating that costimulation through CD28 is not involved in the effector phase of the DTH response in this strain. Our results indicate that the pathology of the DTH response is different in Balb/c compared to B6D2F1 mice, implying that different etiologies are involved in the resultant inflammation.
Analysis of Treg defects in female (NZBxNZW)F1 mice with established disease (48.21)
Authors: Tucker Colleen F , Parnell Sarah A , Alard Pascale , Kosiewicz Michele M 
Published: January 2023

Abstract
(NZBxNZW)F1 (BWF1) is a mouse model of SLE in which females develop nephritis by 36 wks. Sick female BWF1 mice have considerably more Foxp3+ Tregs than age-matched non-sick females and males, but these Tregs are unable to control disease. BrdU uptake by CD4+ (non-Treg) cells was increased in sick female mice, suggesting that CD4 activation/proliferation was not well-controlled in vivo in these mice. However, in in vitro analyses of cells from sick females, no defects in Treg function, responder cell sensitivity to suppression or APC activation of Tregs were detected. CD103+ Tregs, a memory/effector subset, were also increased in sick mice. Vβ TCR usage by CD103+ Tregs differed between sick and non-sick mice suggesting the Treg TCR repertoire, and possibly the antigen specificity of Tregs, could be altered in sick mice. Expression of molecules that affect lymphocyte trafficking was also analyzed. In sick mice, no increases in E-cadherin, the CD103 ligand expressed by activated B cells and epithelium, or other molecules associated with lymphocyte sequestration (e.g., CD62L) in lymphoid organs were detected. However, CXCR3, which is involved in trafficking to inflamed sites, was decreased in CD103+ Tregs from sick mice. These data suggest that features of Tregs other than their inherent regulatory function could be altered in sick mice; however, it is unclear whether this is a cause or an effect of inflammation. Funded by LRI.
EAE induced by a non-Th1/Th17 effector is GM-CSF dependent (48.6)
Authors: Kroenke Mark A , Segal Benjamin M 
Published: January 2023

Abstract
IL-12 and IL-23 modulated CD4+ T cells both have encephalitogenic properties and are capable of inducing experimental autoimmune encephalomyelitis (EAE). Although IL-12 polarized Th1 cells do not make IL-17, it is possible that IL-17 comes into play downstream and is essential for disease pathogenesis. In order to address this possibility, we transferred Th1 cells into IL-17 receptor deficient (IL-17RA -/-) mice. We show that the encephalitogenicity of Th1 cells is not compromised in the absence of IL-17A/F signaling. Furthermore, the adoptive transfer of IL-12 or IL-23 polarized IFNγ -/- CD4+ T cells into wild-type mice is known to induce atypical EAE. Not surprisingly, IL-23 modulated IFNγ -/- T cells lose their encephalitogenic properties upon transfer into IL-17RA -/- mice. In contrast, the transfer of IL-12 modulated IFNγ -/- CD4+ T cells into IL-17RA -/- mice resulted in conventional EAE, demonstrating an absolute requirement for IL-17A/F signaling in atypical EAE. In this model, conventional EAE was completely abrogated by administration of GM-CSF neutralizing antibodies, indicating that GM-CSF can mediate the effector phase of EAE in the absence of IFNγ and IL-17.
Rheumatoid factor autoimmunity in the NZM2410 model combines antigen-specific and polyclonal activation (49.16)
Authors: Niu Haitao , Zhou Zhenhai , Sobel Eric S , Shlomchik Mark J , Morel Laurence 
Published: January 2023

Abstract
The rheumatoid factor (RF) specific AM14 BCR tg model has shown that the activation of autoreactive B cell is antigen (Ag) specific and it bypasses the germinal center (GC) in the MRL/lpr mouse. To characterize the activation pattern of AM14 Id+ (Id+) RF B cells in the Fas sufficient NZM2410 model, we have bred the AM14 HC tg on NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) and B6 mice in the presence or absence of the cognate Ag IgG2aa (TC.IgHa AM14, TC.IgHb AM14, B6.IgHa AM14, and B6.IgHb AM14). Id+ RF cells were relatively excluded from the marginal zone in TC.IgHa AM14 mice and preferentially differentiated into plasmablasts with secretion of Id+ RF in TC.IgHa AM14 as compared to B6.IgHa AM14 mice. Id+ RF secretion was however found in some TC.IgHb AM14 mice, indicating that polyclonal activation can activate autoreactive B cells in this model. BrdU labeling showed that the majority of the Id+ RF secreting cells are proliferating and immunofluorescence showed that the Id+ RF plasmablasts are extrafollicular and bypasses GC in TC.IgHa AM14 mice. In conclusion, Id+ RF B cells break tolerance due to a combination of Ag specific and polyclonal activation bypassing GC on the TC background.
This study is supported by NIH/NIAID R01-A058150
A Novel HLA Shared Epitope VHYLA in Rheumatoid Arthritis (49.5)
Authors: Freed Brian M , Schuyler Ron , Lambert Cherie , Aubrey Michael 
Published: January 2023

Abstract
Although rheumatoid arthritis has long been associated with HLA shared epitopes, a systematic search for epitopes has never been reported. We have developed a computer program that can analyze large HLA data sets and detect all shared epitopes comprising from one to five amino acids. We analyzed high resolution data from the International Histocompatibility Working Group, which included 639 subjects with rheumatoid arthritis and 429 controls, for all combinations of up to five amino acids among HLA-DRB1 positions 9-86. We compared this analysis with a traditional allele analysis and the prevalence of the QRAA epitope. Statistical significance was determined using a Chi-square analysis with a Bonferroni correction. The allele analysis identified three HLA alleles that were positively associated with RA, DRB1*0401 (p=2x10-9), *0404 (p=0.006) and *0405 (p=3x10-5) and five alleles that were resistant, DRB1*0701 (p=0.007), *0801 (p=0.037), *1101 (p=0.037), *1301 (p=0.04) and *1302 (p=0.004). DRB1*0101 (p=0.24) and *0102 (p=0.421) were not associated with RA in this data set. The single amino acid analysis identified V11 (p=10-16), H13 (p=10-16), Y37 (p=10-5), L67 (p=3x10-9), Q70 (p=0.0001) and A74 (p=0.0007) as RA-susceptibility markers. In addition, S11 (p=4x10-7), S13 (p=2x10-6), I67 (p=3x10-7) and D70 (p=5x10-9) were RA-resistance markers. The combination of these positions yielded a VHYLA11,13,37,67,74 epitope that was more strongly associated with RA (p=4x10-22) than QRAA70,71,73,74 (p=9x10-10) or QKAA70,71,73,74 (p=3x10-10). VHYLA is associated with DRB1*0401,*0404,*0405,*0408, *0409 and *0410, but not with DRB1*01 alleles, consistent with the allele analysis in this data set.