bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infection with non-CD4 tropic variant of SIVmac239 accelerates the formation of mature germinal center reactions and elicits antigen specific B cell responses
Authors: Dimopoulos Yiannis Petros , Padhan Kartika , Moysi Eirini , Swanstrom Adrienne , Lifson Jeffrey D , LaBranche Celia , Blaire Robert , Aye Pyone , Schiro Faith , Lackner Andrew , Koup Richard , Petrovas Constantinos , Hoxie Jim 
Published: January 2023

Abstract

Background
What determines the development of germinal centers (GCs) in lymph nodes (LNs) early after HIV/SIV infection is likely to be crucial for developing neutralizing antibodies and B cell memory.

Materials and Methods
Rhesus macaques were inoculated i.v. with either SIVmac239 (n=2) or iMac239ΔD385 (iMacΔD) (n=4), a CD4-independent variant of SIVmac239 lacking a CD4 binding site (J. Virol. 90:4966, 2016). LNs from different time points were analyzed using polychromatic flow cytometry and multiplexed confocal imaging.

Results
In contrast to SIVmac239, iMacΔD infection was associated with relative preservation of total and CD28hiCD95hi memory CD4 T cells, consistent with its compromised capacity to target CD4 T cells. Imaging analysis revealed accelerated formation of mature, polarized GCs in iMacΔD compared to SIVmac239 infected animals, a profile associated with i) increased frequencies of PD-1hiBcl-6hi CD4 T cells, ii) higher levels of IL-10 and IL-21 within the follicles, iii) increased frequency of PH2AX+ (a required factor for isotype switching) B cells, iv) lower levels of Fas-L in the follicular areas, associated with lower TUNEL (cell death) positivity and v) lower accumulation of CD163+ cells (monocytes/macrophages; a surrogate of local inflammation) in proximity to follicles. The observed GC dynamics associate with earlier virus-specific antibody responses in iMacΔD compared to SIVmac239.

Conclusions
Our data indicate that CD4 tropism of SIV greatly affects the development of GC reactions early after infection. The iMacΔD model could provide critical information on how GC reactions can be manipulated to augment the generation of neutralizing antibodies and B cell memory.
Th17 cells confer both systemic and mucosal protection against Trypanosoma cruzi infection
Authors: Cai Catherine Wen , Blase Jennifer R , Eickhoff Christopher S , Hoft Daniel F 
Published: January 2023

Abstract
Chagas disease is caused by chronic infection with the Trypanosoma cruzi parasite. It affects 11 million people, a third of whom will develop life-threatening cardiac and gastrointestinal morbidities. Optimal immunity to this intracellular pathogen requires CD8+ and CD4+ T cell responses. Recently, we demonstrated that CD4+ Th17 cells can confer even stronger protection against T. cruzi infection than CD4+ Th1 cells, typically considered most important for intracellular immunity.
To study systemic protection, we adoptively transferred RAG KO mice with naive polyclonal CD8+ T cells and parasite-specific Th1 or Th17 cells, then infected them subcutaneously. Th17 cell co-transfer resulted in 100% long-term survival, compared to 38% with Th1 co-transfer. Mechanistically, the Th17 cells produced high levels of IL-21, which provided help for the activation of CD8+ T cells. Th17 cells given with IL-21R KO CD8+ T cells failed to protect mice, underscoring the importance of IL-21 signaling.
Although CD8+ T cells were required for systemic immunity, Th17 cells alone protected against mucosal infections. Mice reconstituted with Th17 cells prior to orogastric challenge had decreased parasite burdens in the stomach and lower levels of dissemination to other organs, indicating a direct protective effect. In vitro, we discovered that Th17 cells can directly suppress infection in macrophages via the IL-17A-dependent triggering of NADPH oxidase, important for the phagocyte respiratory burst response.
In summary, we have shown that Th17 cells drive robust systemic and mucosal immune responses against an intracellular parasite through both direct and indirect means, highlighting important new roles for Th17 cells in intracellular immunity.
Itk: A potential target for Saccharopolyspora rectivirgula-induced hypersensitivity pneumonitis
Authors: Koylass Nicholas Robert , Huang Weishan , Carter Chavez , Elmore Jessica , August Avery 
Published: January 2023

Abstract
Hypersensitivity pneumonitis (HP) is a lung disease caused by repeated inhalation of environmental antigens leading to inflammation, tissue scarring, and impaired lung function. This pathology is associated with IL-17A-producing Th17 cells and recruitment of inflammatory cells such as neutrophils to the lungs; on the other hand, Foxp3+ regulatory T (Treg) cells play a protective rolein HP by suppressing pathogenic T cell functions. The thermophile Saccharopolyspora rectivirgula (SR) causes HP in humans, attributed to the rare farmers’ lung disease. We used a murine model carrying the IL-17AGFP/Foxp3RFP dual reporters in SR-induced HP, to study the cellular and molecular mechanisms of HP disease development. IL-2-inducible T cell Kinase, ITK is downstream of the T cell receptor, and is required for effective differentiation of Th17 cells, but limits the expansion of Treg cells. In this work, we sought to determine the possibility of using ITK as a target for pharmaceutical inhibitors in HP. To evaluate the effect of targeting ITK kinase activity in HP therapy, we utilized an Itk allele sensitive mutant (Itkas) that allows specific inhibition by a compound 3MBPP1. WT, Itk−/− and ItkasIL-17AGFP/Foxp3RFP mice exposed to SR were treated with 3MBPP and analyzed for histopathology and various immune cell populations. Intranasal delivery of 3MBPP1 for up to 4 weeks affected pathogenesis and targeted primarily the bronchoalveolarlavage (BAL) immune subsets, including CD4+ IL-17A+ cells. In addition, Treg cells in the pulmonary lymph nodes, neutrophils in the lungs, and γδ T cells in all organs were affected by the treatment. These data suggest that ITK may be a therapeutic target for HP that involves the IL-17 and Foxp3-expressing T cell subsets.
Innate lymphoid cells (ILCs) from septic patients produce higher levels of cytokines than ILCs from healthy controls
Authors: Cruz D David , Niembro-Guerrero Ana Marcela , Ruiz-Sanchez Bibiana Patricia , Arriaga-Pizano Lourdes , Ferat-Osorio Eduardo , Chacon-Salinas Rommel , Estrada-Garcia Iris , Wong-Baeza Isabel 
Published: January 2023

Abstract
Sepsis is a systemic inflammatory response to infection, which leads to life-threatening organ dysfunction. During sepsis, many cells of the innate and adaptive immune systems have functional alterations; in particular, monocytes produce reduced levels of pro-inflammatory cytokines in response to microbial products (MAMPs). Innate lymphoid cells (ILCs) are cells with lymphocyte morphology that lack antigen-specific receptors and respond directly to cytokines and MAMPs; it is not known if ILCs are affected during sepsis. In this study, we used flow cytometry to evaluate the frequency of ILCs in the peripheral blood of septic patients and healthy controls, as well as the expression of CD56, CCR6 and NKp44 and the production of IL-17 and IFN-γ by ILCs. ILCs were defined as CD45+ lineage- CD127+ cells.
The number of total lymphocytes and the number of ILCs were significantly lower in septic patients, compared to healthy controls, with ILCs representing around 0.5% of peripheral blood lymphocytes. In both healthy controls and septic patients, CD56 defines two populations of ILCs: a higher percentage of the CD56− cells express CCR6, compared to the CD56+ cells, while a higher percentage of the CD56+ cells express NKp44, compared to the CD56− cells. CD56− ILCs are the main producers of IL-17, while CD56+ cells are the main producers of IFN-γ, in both healthy controls and septic patients. The production of these two cytokines is increased in the ILCs from septic patients, compared to the ILCs from healthy controls. This is in contrast with the decreased cytokine production that is observed in monocytes and T lymphocytes from septic patients.
This project was funded by CONACyT-México (219661).
Involvement of IL-17A-producing TCR γδ T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection
Authors: Umemura Masayuki , Okamoto-Yoshida Yuko , Yahagi Ayano , Nakae Susumu , Iwakura Yoichiro , Takaesu Giichi , Matsuzaki Goro 
Published: January 2023

Abstract
Interleukin (IL)-17A is a cytokine originally reported to induce neutrophil-mediated inflammation and anti-microbial activity. The CD4+ T cells which produce IL-17A have been well characterized as Th17 cells. On the other hand, IL-17A-producing TCR γδ+ T cells have been reported to participate in the immune response at an early stage of infection with Listeria monocytogenes and Mycobacterium bovis in mice. However, the involvement of IL-17A in protective immunity was not clearly demonstrated in the chronic stage of M. tuberculosis-infected mice. In this study, we found that TCR γδ+ T cells are a primary source of IL-17A, but that mycobacterial antigen-specific Th17 cells were hardly detected even at the chronic stage of M. tuberculosis infection. IL-17A-deficient mice showed a decreased survival rate, and increased bacterial burden in the lungs after the infection when compared to the wild-type mice. Furthermore, a histological analysis showed an impaired granuloma formation in the infected lungs of IL-17A-deficient mice, which was considered to be due to a decrease of IFN-γ and TNF-α at the chronic stage. These data suggest that the IL-17A-producing TCR γδ+ T cells, rather than the Th17 cells, in the infected lungs are an indispensable source of protective immunity against M. tuberculosis infection.
The role of IL-10 during early M. tuberculosis infection in a non-human primate model
Authors: Wong Eileen A , Kraus Carolyn , Reimann Keith A , Flynn JoAnne L 
Published: January 2023

Abstract
Tuberculosis (TB), caused by M. tuberculosis (Mtb), continues to be a global health problem. Lung granulomas, organized structures of host immune cells to contain Mtb, are the pathologic hallmark of TB. T cell cytokines play a major role in containment of Mtb infection within these granulomas. While the importance of pro-inflammatory cytokines IFN-γ and TNF in controlling Mtb infections has been established, the effects of immunomodulatory cytokines, such as IL-10, in Mtb infections are less well understood. We used cynomolgus macaques, a non-human primate (NHP) model that recapitulates human TB to investigate the role of IL-10 early in Mtb infection. Preliminary ex vivo studies of excised lung granulomas from Mtb-infected NHPs suggested IL-10 may be downregulating IL-2 cytokine production in TB lung granulomas. To further examine the role of IL-10, a cross-reactive, rhesus recombinant anti-IL-10 antibody was used to neutralize IL-10 in vivo in NHPs prior to and during the course of Mtb infection. Peripheral cytokine responses in the presence of IL-10 neutralization were analyzed serially by flow cytometry of peripheral blood mononuclear cells. Disease progression was monitored by PET-CT scans, and local immune responses in the granulomas assessed at necropsy. Our data indicate transient differences in inflammation early in infection between anti-IL-10-treated and control monkeys. Surprisingly, there was less inflammation in granulomas from IL-10 neutralized animals at 3–4 weeks post-infection, compared to control animals. Overall, this unique dataset provides important insight into the contribution of IL-10 to the necessary immunological balance for controlled bacterial burden and disease pathology in Mtb infections.
Role of p38 MAPK and NF-κB signaling in chromatin decondensation and acquisition of cytokine competence during T cell activation
Authors: Rawlings Jason S , Funsten Jen , Brizuela Keny Murillo , Bingham Kellie , Lee Megan , Mitchell Taylor , Meredith Jenna 
Published: January 2023

Abstract
A proper immune response is hallmarked by the activation and clonal proliferation of antigen specific T cells. Antigen presentation to the T cell receptor (TCR) leads to the production of two signaling molecules, IP3 and DAG. While IP3 induces calcium flux, DAG activates Protein Kinase C (PKC). The activation of these pathways results in the decondensation of chromatin and the production of interleukin-2 (IL-2), both of which are required for the clonal proliferation of activated T cells. Previous work in our lab demonstrated that the IP3 pathway is sufficient for chromatin decondensation. In this study, we show that this pathway is not sufficient to make cells respond to IL-2. Furthermore, we investigate the role of the DAG pathway, specifically the role of the downstream molecules p38 MAPK and NF-κB, in the decondensation of chromatin and the competence to respond to IL-2 signaling. We found that neither of these molecules play a role in chromatin decondensation and that NF-κB may play a role in IL-2 competence. Collectively, these data, along with our previous findings, suggest that chromatin decondensation and competence to respond to IL-2 may be controlled by IP3 and DAG signaling respectively.
IRF4 controls a core regulatory circuit of T cell dysfunction in transplantation
Authors: Wu Jie , Shi Xiaomin , Xiao Xiang , Minze Laurie , Wang Jin , Ghobrial Rafik M. , Xia Jiahong , Sciammas Roger , Li Xian C. , Chen Wenhao 
Published: January 2023

Abstract
T cell dysfunction has emerged as a key event leading to failure in the control of persistent infections and tumors. However, the transcriptional determinants for T cell dysfunction remain unknown. Here we show that IRF4 is a key transcriptional determinant of T cell dysfunction by restraining the dysfunctional differentiation process.
We use a heart transplantation model to decipher the molecular basis of T cell dysfunction. Heart allografts survived indefinitely in Irf4-deficient mice. This stable engraftment is due to the progressive establishment of effector T cell dysfunction. Mechanistically, IRF4 represses PD-1, Helios, and other molecules associated with T cell dysfunction. In particular, IRF4 has a profound impact on epigenetic accessibility of PD-1 cis-regulatory elements. In the absence of IRF4, chromatin accessibility as well as binding of Helios at PD-1 cis-regulatory elements are markedly increased in effector T cells, resulting in enhanced expression of PD-1 and T cell dysfunction. Intriguingly, although the dysfunctional state of Irf4-deficient T cells is initially reversible by blockade of PD-1/PD-L1 pathway, it progressively evolves into a “terminal” irreversible state within 30 days post-transplant. Lastly, we revealed that the MEK1/2 inhibitor, trametinib, dramatically decreases IRF4 expression in T cells, abrogates EAE development, and prolongs heart allograft survival.
Our results reveal a previously unappreciated aspect of T cell dysfunction, namely the repression of the dysfunctional differentiation of T cells by IRF4. Central control of T cell dysfunction by IRF4 has a significant potential impact on the course of future work in modulating T cell dysfunction
Celecoxib down-regulates Angiogenic factor of Retinal Pigment Epithelial cells in Hypoxic state via HIF-1α degradation.
Authors: KIM SEONHYUN , KIM JAYOUNG , HONG SEUNGWOO , KIM YEONGSEOK , HUR DAEYOUNG 
Published: January 2023

Abstract
Age-related macular degeneration (AMD) is a common disease causing blindness in the aging population. AMD affects central regions of the retina and choroid that can lose vision. This disease starts with drusen between retinal pigment epithelium(RPE) and Bruch’s membrane and finally results in neovascularization and destruction of retina. Hypoxic state is deeply associated with abnormal vessel formation in AMD. Hypoxia accumulate hypoxia-inducible factor-α(HIF-1α) and induce angiogenesis. In this study, we investigated that HIF-1α was upregulated in ARPE-19 cells which was exposed hypoxic states. Interestingly, celecoxib, an inhibitor of cyclooxygenase-2 (COX-2) could degrade HIF-1α on hypoxic RPE cells. We also observed that celecoxib blocked vascular endothelial growth factor (VEGF) production in hypoxic ARPE-19 cells, and conditioned media of celecoxib-treated ARPE-19 cells inhibited tube formations of HUVECs. We investigated that celecoxib might regulate degradation by ubiquitination/proteasome system, which were supported by MG-132, PYR-41 pretreatment experiments. Taken together, we suggest that these effects of celecoxib down-regulate angiogenesis through HIF-1α degradation and can support prevention of neovascularization of AMD.
The Nrf2 activators tBHQ and CDDO-Im have both Nrf2-dependent and – independent effects on human Jurkat T cell activation, as determined by CRISPR-Cas9 gene editing
Authors: Zagorski Joseph Ward , Maser Tyler P , Liby Karen T , Rockwell Cheryl Elizabeth 
Published: January 2023

Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a stress activated transcription factor, activated by such stimuli as reactive oxygen and electrophilic stress. Upon activation Nrf2 accumulates in the nucleus and activates a battery of target genes, many of which are cytoprotective in function. We have previously shown that a common synthetic food additive, tBHQ, is a potent Nrf2 activator and suppresses certain events of human T cell activation, namely, IL-2 secretion, CD25 expression, and transactivation ability of NFkB. The purpose of our current studies was to develop a Nrf2-null human model, in which it can be determined whether the effects of tBHQ upon the early events of T cell activation are Nrf2-dependent. Treatment of both Wild-type and Nrf2-null Jurkat T cells revealed that the suppression of IL-2 and NFkB by tBHQ is largely Nrf2-independent, whereas the suppression of CD25 is partially dependent upon Nrf2. Although interesting, these studies left the question as to the role of Nrf2 in T cell activation largely unanswered. Therefore, we utilized a more potent and selective Nrf2 activator, CDDO-Im. CDDO-Im treatment resulted in a Nrf2-dependent suppression of IL-2 secretion and an inhibition of NFkB activity that was partially Nrf2-dependent. Taken together, our model is the first to show that activation of Nrf2 suppresses early events of human T cell activation (This work is funded by NIH grants ES018885, ES024966 and GM092715).
Determining Fas Signaling Pathways by Quantifying Receptor Clustering
Authors: Frazzette Nicholas , Cruz Anthony , Sengupta Prabuddha , Lippincott-Schwartz Jennifer , Siegel Richard M. 
Published: January 2023

Abstract
The TNF-cytokine family receptor Fas (CD95) mediates T cell apoptosis by recruiting a death-inducing signaling complex (DISC) composed of the adaptor protein (FADD) and Caspase-8. Recently, it has been shown that Fas is also directs non-death signaling and enhances effector cell differentiation in T cells. Mutations which reduce the ability of Fas to localize to lipid raft microdomains and cluster upon activation abrogate the death-inducing potential of Fas while preserving non-apoptotic signaling. Caspase-8, a key mediator of both apoptotic and non-apoptotic signal, has been shown to form filamentous structures in vitro and upon overexpression in mammalian cells, but it is unknown if this process occurs in vivo to facilitate signaling. To investigate these supramolecular phenomena, we developed Fas and Caspase-8 fused to photoactivatable fluorescent proteins to be expressed in both primary T cells and T cell lines for super resolution imaging. Additionally, we have produced supported planar lipid bilayers presenting Fas ligand (FasL) and T cell stimulatory ligands to mimic a physiologic signaling environment. Photoactivatable localization microscopy (PALM) is used to observe and quantify clustering Fas molecules and formation of caspase-8 containing signaling complexes at nanometer scale resolution. Structure illuminated microscopy (SIM) and PALM will be used to observe the behavior of Fas relative to cellular-scale actin remodeling and TCR clustering. Our findings will reveal the behavior of supramolecular complexes mediating apoptosis and non-apoptotic signaling by Fas in the plasma membrane of living cells.
Alterations in B cell compartment induced by aging and impact of HIV infection.
Authors: Rinaldi Stefano , Pallikkuth Suresh , George Varghese , de Armas Lesley , Pahwa Rajendra , Sanchez Celeste , Pallin Maria , Pan Li , Cotugno Nicola , Dickinson Gordon , Rodriguez Allan , Fischl Margaret , Alcaide Maria , Gonzalez Louis , Palma Paolo , Pahwa Savita 
Published: January 2023

Abstract
Perturbations in B cells occur in both, chronological aging and in HIV infection. We investigated B cells in young (Y, &lt;40yr), middle (M, 40–59yr) and old (O, ≥60yr) influenza vaccinated participants with controlled HIV infection (HIV, n=64) and HIV negative healthy controls (HC, n=60) at pre-vaccination (T0) and post-vaccination on d7 (T1) and d21 (T2). Results of B cell immunophenotyping of T0 PBMC were correlated against measures of vaccine responsiveness (hemagglutination inhibition (HAI) titers and antibody secreting cells in ELISpot) and age. Both HC and HIV demonstrated a negative correlation of age and Flu-specific HAI titer at T2 (p=0.005, and 0.019, respectively). However only HC demonstrated negative relationships of age with spontaneous ELISpot for plasmablast function at T1 (p=0.0001) and memory B cell ELISpot at T2 (p=0.05). Immunophenotyping of B cells in HC demonstrated increased double negative (DN) B cells and decreased plasmablasts in O compared to Y. In HIV however phenotypic and functional impairment of B cells were already evident in Y such that Y HIV were different from Y HC with increased DN B cells and decreased B ELISpot responses, while O HIV were similar to O HC. Additionally, B cells from Y HIV had increased frequencies of CD80 and PDL1 markers suggesting a heightened state of immune activation and exhaustion. Our results suggest that despite virological suppression, young HIV-infected individuals are similar to Old HC because of early impairment of B cells due to ongoing immune activation. Clinical implications are that vaccination strategies used for old HC may need to be implemented at an earlier age for HIV infected population for improved vaccine efficacy.
Multifunctional cytokine and T cell memory phenotype profiles differ in active versus cured tuberculosis.
Authors: Leong Samantha , Rodrigues Rodrigo Ribeiro , Ellner Jerrold J. , Dietze Reynaldo , Jones-López Edward C. , Alland David , Salgame Padmini 
Published: January 2023

Abstract
Tuberculosis, one of the most prevalent and deadliest infectious diseases worldwide, requires long-term multidrug treatment regimens for curing active clinical disease. However, a diagnostic method for identifying successful cure from TB disease following anti-TB chemotherapy remains elusive. The overall goal of this study was to assess differential patterns of cytokine production and memory T cell phenotypes to distinguish between active TB subjects and remotely cured TB individuals. Using peripheral blood mononuclear cells from subjects enrolled in a TB household contact study established in Vitória, Brazil, cells were stimulated ex vivo with TB antigens and evaluated using multi-parametric flow cytometry. Total cytokine and multifunctional cytokine analyses revealed an increase in the proportion of IL-17 producing CD4+ T cells in active TB subjects, while cured TB subjects showed a clear dominance of cells producing IFNγ and IL-2 or TNFα. Comparison of memory phenotypes revealed differences between proportions of several CD4+ T cell memory subsets, with an effector memory dominance in cured TB compared to an increased stem cell memory representation in active TB. Increased expression of exhaustion marker PD-1 in advanced stages of memory cell differentiation suggested its possible use as a surrogate indicator of memory subset fluxes, with possible application as a biomarker for distinguishing differences between cured TB and active TB individuals.