bluuebunny/crossref_metadata_2025_split huggingface dataset:
The AP1 transcription factor JunB is necessary for cell survival of activated CD4+ T cells
Authors: Hsieh Tsunghan , Sasaki Daiki , Taira Naoyuki , Chien Hsiaochiao , Sarkar Shukla , Ishikawa Hiroki 
Published: February 2023

Abstract
JunB, an AP-1 transcription factor, interacts with BATF and IRF4 and plays an essential role for differentiation of Th17 cells and effector T regulatory cells. BATF and IRF4 are also important for differentiation of Th1 and Th2 cells, but the role of JunB in those cells is largely unknown. Here we demonstrate that JunB is necessary for survival of Th1 and Th2 cells. JunB is homogenously induced in activated CD4 T cells, and Junb deficiency severely impairs the clonal expansion of those cells in mice immunized with adjuvants that induce Th1, Th2 and Th17 responses. Like BATF and IRF4, JunB promotes cell survival through repressing apoptosis in Th1, Th2 and Th17 cells. However, unlike BATF and IRF4, JunB is not required for regulation of cellular metabolism in those cells. Junb deficiency results in increase of expression of Th1 signature cytokine IFN-γ but does not affect expression of Th2 signature cytokines IL-4 and IL-13 in vivo. Mechanistically, JunB binds to a locus of Bcl2l11 together with BATF and IRF4 and inhibits its product Bim, an apoptosis inducer. Although JunB-mediated chromatin remodeling was observed, it was not linked with the regulation of Bcl2l11, Ifng and Il13. In conclusion, JunB is an essential transcription factor that cooperate with BATF and IRF4 to regulate activated CD4 T cell survival.
Development of group-3 innate lymphoid cells via Tox2-dependent pathway in gut.
Authors: Das Arundhoti , Wang Yueqiang , Lu Xiaoxiao , Kaye Jonathan , Bhandoola Avinash 
Published: February 2023

Abstract
Innate lymphoid cells (ILCs) are immune cells that lack specific antigen receptors but possess similar effector functions as T cells. Interestingly, ILCs and T cells express many of the same transcription factors. One such factor is TOX, a sequence non-specific nuclear transcriptional regulator that is crucial for development of both CD4 T cells and ILCs. TOX-deficient mice have significantly reduced number of early innate lymphoid progenitors (EILP) and ILC progenitors (ILCP). Consequently, the mature NK cells, ILC1, ILC2 and ILC3 subsets are greatly reduced in Tox−/− mice. Interestingly ILC3 numbers in gut are not reduced by the absence of TOX. We have discovered that TOX2, another member of the TOX family of HMG-box proteins, is highly expressed in ILC precursors. We generated Tox2−/− mice and found they have reduced ILC3 in gut; however, ILC3 cells in spleen or lymph node are intact. We also observed ILCP in fetal gut and adult gut were significantly reduced in Tox2−/−mice suggesting TOX2 is required for gut ILC3 development. However, ILCP numbers in adult gut of Tox−/− mice were unaffected. We are currently performing single-cell RNA-sequencing on gut ILC3 from Tox2−/− and Tox−/− mice to transcriptionally characterize these cells and to identify the heterogeneity within the ILC3 population. Taken together, our results indicate the existence of at least two pathways of ILC development: a central pathway in bone marrow and fetal liver that is TOX dependent; and a peripheral pathway of development of ILC3 in gut that requires TOX2.
Kdm6b regulates the generation of effector CD8+ T cells by inducing chromatin accessibility in effector-associated genes
Authors: Xu Tianhao , Schutte Alexander , Jimenez Leandro , Gonçalves Andre N.A. , Keller Ashleigh , Pipkin Matthew E. , Nakaya Helder , Pereira Renata M. , Martinez Gustavo J. 
Published: February 2023

Abstract
The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs respectively. Here, we demonstrate that the Lysine Demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific KO mice or knockdown utilizing shRNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.
ABCB7 deficiency causes ferroptosis in peripheral T cells
Authors: Lehrke Michael Jonathan , Belmonte Paul , Kennedy Madeleine , Rajcula Matthew , Shapiro Virginia Smith 
Published: February 2023

Abstract
ABCB7 exports iron-sulfur (Fe-S) clusters from the mitochondria into the cytoplasm. Conditional deletion of ABCB7 revealed that it is required for peripheral T cell homeostasis. CD4-cre ABCB7 cKO mice have normal thymic development, but a severe reduction in peripheral T cell numbers. A majority of the peripheral T cells in the ABCB7 cKO mice were recent thymic emigrants (RTEs), indicating a loss of more mature T cells in the periphery. T cell maturation markers were found to be normal and stimulation of ABCB7 cKO RTEs revealed normal levels of TNFα production. These data indicate that the loss of peripheral T cells in CD4-cre ABCB7 cKO mice was not due to a defect in development or maturation but a defect in peripheral homeostasis. ABCB7-deficient T cells did not have evidence of elevated apoptosis. We demonstrated iron accumulation was occurring in ABCB7-deficient peripheral T cells using the metal-specific dye Phen Green SK. Additionally, lipid peroxides levels were elevated in the ABCB7 cKO T cells. Lipid peroxides are a hallmark of ferroptosis, an iron-dependent form of regulated cell death. Expression of GPX4, the master regulator of ferroptosis, was normal in ABCB7 cKO T cells. In addition, levels of glutathione, which counteracts lipid peroxides were found to be normal, indicating the ferroptosis protection pathway was intact and that the iron overload was causing ferroptosis. Interestingly, treatment with the iron chelator deferoxamine did not rescue peripheral T cells in the CD4-cre ABCB7 cKO mice. Vitamin E, a potent antioxidant, also failed to rescue peripheral T cell homeostasis. Thus, ABCB7 is required to maintain iron homeostasis and its loss leads to peripheral T cell ferroptosis.
Blockade of the CD6-ALCAM pathway modulates effector T cell function
Authors: Ampudia Jeanette , Chu Dalena , Badrani Jana , Doherty Taylor , Connelly Stephen , Ng Cherie 
Published: February 2023

Abstract
CD6 is a T-cell costimulatory receptor predominantly expressed on T cells and promotes immune synapse formation, T-cell activation, and T-cell migration via interaction with activated leukocyte cell adhesion molecule (ALCAM). The CD6-ALCAM pathway has been linked to the pathogenesis of multiple autoimmune and inflammatory diseases. While the contribution of CD6 to T cell activation has been well described, less is known regarding the expression levels and role of CD6 on effector and memory T cells which contribute to ongoing disease. Consequently, the aim of this study was to determine the role of CD6 specifically on Th1, Th2 and Th17 effector T cells (Teff). Blockade of the CD6 pathway using itolizumab, a humanized mAb currently being tested in the clinic, during restimulation of fully differentiated Th1, Th2 or Th17 Teff cells in the presence of ALCAM inhibited multiple effector functions, including proliferation and changes in cell size. An average 40% decrease in proliferation was observed across multiple donors. Furthermore, treatment of Teff cells with itolizumab resulted in a significant decrease in relevant cytokines such as IFNγ and TNFα for Th1, IL-4 and IL-13 for Th2, TNFα and IL-17 for Th17, as well as in expression levels of T cell markers of activation and exhaustion such as CD69, CD25, and PD-1. This effect was exclusively observed in the presence of ALCAM, indicating that the effect was specific to blockade of the CD6-ALCAM pathway. This study is the first to characterize the CD6-ALCAM pathway as a key regulator of effector Teff cell function. As these are the cells that drive disease pathogenicity, these data support targeting the CD6-ALCAM pathway to inhibit effector Teff cell populations in autoimmune and inflammatory diseases.
IL-23 maintains tissue resident memory Th17 cells in murine and psoriatic skin
Authors: Whitley Sarah K , Li Mushi , Tabib Tracy , Weaver Casey T , McGeachy Mandy J , Lafyatis Robert A , Kaplan Daniel H 
Published: February 2023

Abstract
Tissue resident memory Th17 cells (TRM17) are the key cell type driving the chronic skin inflammation of psoriasis. Although IL-23 is strongly associated with autoimmunity and chronic inflammatory disorders including psoriasis, and anti-IL-23 biologic agents have remarkable efficacy in the treatment of psoriasis, the precise role of IL-23 in supporting IL-17-mediated skin inflammation remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from C. albicans skin infection, and TRM17 mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23R antibody to dual Il17aCre Rosa26CAG-fl/fl-tdTomato Il17fThy1.1/Thy1.1 (17Fate) fate reporter mice following resolution of primary C. albicans infection resulted in a selective reduction in the number of CD69+CD103+TRM17 cells in skin compared with isotype controls. TRM17 proliferation was reduced and survival was unaffected. CD301b+ dermal dendritic cells (dDC) were an obligate source of IL-23 that supported TRM17 maintenance in skin after C. albicans challenge. These data demonstrate that locally produced IL-23 promotes in situ TRM17 proliferation to support their long term retention in skin. In normal human skin, we identified dermal cDC2 as the principal source of IL-23, although keratinocytes and CD4+ T cells were additional sources of IL-23 in psoriasis skin. Analysis of human psoriasis skin before and after clinical anti-IL-23 therapy revealed reduced TRM17 number and proliferation index, suggesting that targeted depletion of pathogenic TRM17 is the major mechanism by which anti-IL-23 therapy induces uniquely durable disease-free intervals in psoriasis patients.
Studying lymphocyte differentiation in the spleen via spatial transcriptomics
Authors: Williams Cameron Gerard , Engel Jessica A. , Soon Megan S.F. , Murray Evan , Chen Fei , Haque Ashraful 
Published: February 2023

Abstract
Immune cell positioning within secondary lymphoid tissues likely affects cell-cell interaction and subsequent immune responses. Techniques such as intra-vital imaging and multiplex immunohistochemistry provide insight into this, but require specialist reagents. To examine cell-cell interactions in dense tissue at whole-genome scale, we tested the feasibility of a single-cell spatial transcriptomics method, Slide-seq2. We first confirmed using murine gut tissue that small tertiary lymphoid structures, particularly rich in B cells, could be identified and examined at a cellular level in the small intestine. We then hypothesized that microanatomical alterations could be detected. To test this, we compared mouse spleens before and 7 days after infection with blood-stage malaria parasites. To increase the molecular resolution of our data, we integrated Slide-seq2 data with high-depth, droplet-based, scRNA-seq data, generated via Chromium controller from 10× Genomics. We found that Slide-seq2 produced sufficiently rich data to map cell types from an scRNA-seq reference. Some spatially defined transcriptomes appeared to derive from mixtures of cell types, indicating that further deconvolution of spatially resolved transcriptomic data was required. Via unsupervised clustering of whole transcriptomes, we confirmed that T and B cell zones within naïve mice became less ordered at the peak of malaria infection, reflecting T and B cell interaction. Ongoing analyses aim to define novel splenic T and B cell interactions during malaria, both in extra follicular areas as well as within the germinal center.
Histone deacetylase-1 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
Authors: Moreira Jôsimar Dornelas , Vankayalapati Ramakrishna , Samten Buka 
Published: February 2023

Abstract
Although IL-1b is required for the protection against Mycobacterium tuberculosis (Mtb) infection, its uncontrolled production is associated with chronic inflammation and lung damage in Tuberculosis. Epigenetic effector molecules histone deacetylases (HDACs) play critical roles in tumorigenesis and immune regulation, however their roles in IL-1β production remain unexplored. Initial screening of 11 variants of HDAC with their chemical inhibitors identified that inhibition of HDAC-1 promotes secretion of IL-1β and increases the lysine acetylation of histone H3 by primary macrophages and dendritic cells (DCs) in response to LPS/CD40L, IFN-γ stimulation or Mtb infection without affecting pro-IL-1β and IL-6. Inhibition of NLRP3 or Caspase-1 reversed this effect of HDAC-1 inhibition without affecting cell viability, implying the involvement of NLRP3 inflammasome activation. Consistently, HDAC-1 inhibition further elevated the expression of both mRNA and protein of NLRP3 in macrophages and DCs under stimulation and increased levels of cleaved Caspase-1 and mature IL-1β in the culture supernatants. Mtb infection and stimulation with LPS/CD40L of these cells induced increased expression and phosphorylation of HDAC-1 and increased HDAC-1 activity in cell lysates which was suppressed by HDAC-1 inhibitor. Treatment of low dose aerosol Mtb-infected mice with HDAC-1 inhibitor increased IL-1β in mice lungs without affecting IL-6 production. These suggest that HDAC-1 controls IL-1β maturation via regulation of NLRP3 expression and activation, thus suggesting a novel mechanism for the regulation of IL-1β, a major inflammatory cytokine in tuberculosis infection and other inflammatory diseases.
Maternal Schistosomiasis Hinders B Cell Development Leading to Reduced Humoral Immunity Upon Immunization
Authors: Gibbs Lisa C , Oviedo Juan Marcos , Fairfax Keke 
Published: February 2023

Abstract
Maternal helminth infections are a global public health concern that correlate with altered infant immune responses to childhood immunizations and infection. A mechanistic understanding of how maternal helminth infection alters the immune responses of offspring is critical to improve childhood vaccine regimens in endemic areas, decrease childhood morbidity, and to understand the consequences of specific defects in long-lived immunity. Our murine model of maternal Schistosoma mansoni infection demonstrated that pups born to mothers chronically infected with Schistosoma mansoni have reduced IL-4 production and B cell expansion. This defect continues following tetanus/diphtheria immunization, resulting in impaired immunity. To determine the origin of this humoral immunity defect, we began investigating lymphoid progenitors. We found an increase in the common lymphoid progenitors (CLPs) in the bone marrow of naïve mice from infected mothers. When immunized with a Tetanus/Diphtheria vaccination, there is a significant reduction in expansion of these progenitors in comparison to age matched controls from uninfected mothers coupled with a decrease in bone marrow B cells. RNA sequencing revealed a defect in stem cell pluripotency signaling pathway. Further analysis post-immunization shows a decrease in immature B cells in the bone marrow of pups from infected mothers, suggesting a more exclusive selection process or differential selective pressure, leading to lower B cell frequencies in the draining lymph node. We hypothesize that altered transcriptional regulation at the progenitor level caused by maternal Schistosomiasis is the mechanistic root of long-lived defects in humoral immunity to foreign antigens.
High resistance to intestinal nematode infection is associated with a strong bias for TFH cell responses, rapid IgG1 class switch and limited Th2 effector cell expansion
Authors: Zhang Hongwei , Rausch Sebastian , Hartmann Susanne 
Published: February 2023

Abstract
Gastrointestinal nematode infections are highly prevalent in nature, lead to considerable morbidity in infected humans and cause high economical loss in animal husbandry. While it is clear that type 2 responses orchestrated by CD4+GATA-3+ Th2 cells are pivotal for the control of GI nematodes, the basis for differential susceptibility of distinct host genetic backgrounds is less well understood.
The high resistance of ‘rapid responder’ SJL mice to infections with the small intestinal nematode H. polygyrus is evident in low parasite egg production and the termination of infection within a few weeks. Comparing the SJL line to slow responder C57BL/6 mice, we found that SJL mice generated relatively few Th2 effector cells, many follicular T helper cells and strong antibody responses in spleen and gut draining lymph nodes. These Th2 effector cells of SJL mice expressed high levels of the gut/mucosal homing markers CCR9/a4b7, resulting in the rapid accumulation of Th2 cells in the infected small intestine. Surprisingly, resistance was further associated with exceptionally high proportions of Treg in the spleen of SJL mice at steady state and the vigorous expansion of Treg in mLN after infection. This coincided with a bias for follicular T helper cells expansion in both mLN and spleen and, consequently, more extensive IgG1 class switching by GL7+ germinal center B cells in both organs. Infection-derived B cells transfer provides protection in SJL mice, not in B6 mice.
In conclusion, resistance versus susceptibility to primary H. polygyrus infection appears to be less dependent on the overall magnitude of Th2 responses, but rather seems to depend on rapid Th2 effector homing, follicular T helper cells and the rapid instruction of antibody responses.
IL-21 is necessary to both induce and sustain humoral immunity to Plasmodium
Authors: Surette Fionna , Butler Noah 
Published: February 2023

Abstract
Resistance to malaria depends on the generation of antibodies derived from germinal center (GC) responses. T follicular helper (Tfh) cells play a critical role in the selection of high-affinity GC B cells that can differentiate into either memory B cells or antibody secreting plasma cells. Mice deficient in IL-21 or its receptor fail to mount GC responses, secrete parasite-specific IgG and control primary Plasmodium infections. However, whether IL-21 exerts temporally distinct contributions to either the maintenance of GC reactions or memory, during primary anti-Plasmodium humoral immunity or memory recall responses, is not known. We hypothesize that CD4+ T cell derived IL-21 acts to support the maintenance of GC B cells and is critical for secondary humoral immune reactions orchestrated by memory Tfh. To test this hypothesis, we utilized IL-21-VFP reporters and developed cell type-specific and conditional IL-21 knockout systems. Our data show that Tfh-derived IL-21 expression peaks during the first week of infection as GC are initially forming. Following tamoxifen mediated deletion of CD4 derived IL-21 during an established GC reaction (days 16–18 p.i.), we observed significant reductions in GC B cells and loss of memory B cell-derived, parasite-specific IgG production following challenge. Thus, in addition to inducing GC responses, our experiments show that IL-21 is critical for sustaining GC responses and the formation of functional memory B cell responses.
Dual GM-CSF and IL-17A expressing CD8+ T cells mediate vaccine-immunity, but not immunopathology, against lethal fungal pneumonia in CD4+ T-cell deficient hosts
Authors: Nanjappa Som G. , Mudalagiriyappa Srinivasu 
Published: February 2023

Abstract
Opportunistic fungal infections are rising at alarming rates in immunocompromised individuals. There is no licensed fungal vaccine available, nor there a clear understanding of the protective host responses. In a mouse model of fungal vaccine-immunity in CD4+ T-cell lymphopenia, we have previously shown that vaccine-induced IL-17A producing CD8+ T (Tc17) cells are necessary for controlling lethal fungal pneumonia. However, we found a significant number of Tc17 cells that co-expressed GM-CSF (&gt;50%), but their role has been implicated as ‘pathogenic’ in autoimmune disorders. In this study, using state-of-the-art approaches, we found that GM-CSF +Tc17 cells are essential for vaccine-immunity against lethal fungal pneumonia without precipitating an adverse immunopathology. Induction of GM-CSF+Tc17 cells, following vaccination, required signaling from cytokines, IL-1 and IL-23, that promoted differentiation and proliferation of effectors. Unexpectedly, IL-23 was dispensable for memory homeostasis of GM-CSF+Tc17 cells. Following the lethal pulmonary fungal challenge, IL-23 was required for the GM-CSF+Tc17 cells responses, but not for their re-differentiation, and was necessary to mitigate the immunopathology of the lungs. Collectively, GM-CSF+Tc17 cells are required for vaccine-mediated immunity against lethal fungal pneumonia.
Comparative Evaluation of Fibrin Network Formation after Root Conditioning using Erbium, Chromium-Doped Yttrium Scandium Gallium and Garnet Laser, Ethylene-Diamine-Tetra-Acetic Acid, and Tetracycline on Dentin: A Scanning Electron Microscopic Study
Authors: Satish Riya Liza , Peter Maya Rajan , Bhaskar Anuradha , Vylopillil Rajesh , Balakrishnan Biju , Suresh Reshma 
Published: February 2023

Context:
Regeneration of periodontal tissues depend on the adhesion and development of fibrin clots to the root surface. Demineralization of the root surface ensures removal of smear layer uncovering dentin tubules and collagen matrix. Root conditioning agents were introduced to remove the smear layer and enhance the adhesion of blood components.

Aims:
The aim of the study was to determine the effect of erbium, chromium-doped yttrium, scandium, gallium and garnet (Er, Cr: YSGG) laser on smear layer removal (SLR) and fibrin network formation when compared to tetracycline, and ethylene-diamine-tetra-acetic acid (EDTA) for periodontal regeneration.

Settings and Design:
The study was conducted at Amrita school of dentistry and the study design involves in vitro comparative study.

Subjects and Methods:
Forty dentinal sections were prepared from freshly extracted teeth that were periodontally affected. The samples were divided into four groups: Scaling and root planing (SRP), tetracycline, EDTA, and Er, Cr: YSGG laser. The samples were assessed using a scanning electron microscope and photomicrographs were taken and analyzed for removal of smear layer, blood component adhesion (BCA), and fibrin network formation.

Statistical Analysis Used:
Analysis of variance test and Kruskal–Wallis test with P < 0.05 considered to be statistically significant.

Results:
There was a significant difference between Er, Cr: YSGG laser, tetracycline hydrochloride, and EDTA categories when compared with SRP categories. There was no significant difference between Er, Cr: YSGG laser, tetracycline, and EDTA according to SLR scoring and BCA scoring.

Conclusions:
It can be concluded that Er, Cr: YSGG laser-treated samples presented complete elimination of smear layer, formation of fibrin network, and BCA along with desensitizing effect for a better reduction in dentin hypersensitivity.