bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of LGP2-dependent regulation of RIG-I signaling and dendritic cell activation
Authors: Quicke Kendra , Suthar Mehul S 
Published: January 2023

Abstract
Pattern recognition receptor (PRR) signaling is essential for regulating innate and adaptive immune responses to infection. The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are a family of PRRs that, upon binding non-self RNA, trigger robust antiviral immune responses characterized by expression of type I interferon (IFN), pro-inflammatory cytokines, and antiviral effector genes. The RLR LGP2 is a known regulator of the RIG-I signaling pathway, however, the underlying mechanism by which LGP2 regulates RIG-I signaling and antiviral defense is poorly understood. Thus, we utilized a highly specific RIG-I agonist to evaluate the impact of LGP2 on RIG-I signaling independent of virus-mediated effects. We performed transcriptional profiling studies in dendritic cells and found that genetic ablation of LGP2 leads to an enhanced and broader type I IFN transcriptional program, characterized by increased type I IFN, proinflammatory cytokine and antiviral gene expression. To define the negative regulatory mechanism of LGP2, we performed biochemical and molecular analyses and found: 1) RNA binding and ATP hydrolysis functions of LGP2 are dispensable for inhibition of RIG-I signaling; 2) the C-terminal repressor domain of LGP2 is not required for RIG-I signaling inhibition; and 3) LGP2 inhibits RIG-I ubiquitination by forming a complex with TRIM25, an E3 ubiquitin ligase that post-translationally modifies RIG-I into a signaling ‘active’ form. Based on these results, we believe LGP2 negatively regulates RIG-I-specific signaling by inhibiting RIG-I activation. These findings demonstrate an important, yet underappreciated, role for LGP2 in regulating inflammation and dendritic cell responses during virus infection.
The mitochondrial E3 ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signaling.
Authors: Yoo Young Suk , Park Yong-Yea , Lee Jong-Soo , Cho Hyeseong 
Published: January 2023

Abstract
Mitochondria serve as platforms for innate immunity. The mitochondrial antiviral signalling (MAVS) protein forms aggregates that elicit robust type-I interferon induction on viral infection, but persistent MAVS signalling leads to host immunopathology; it remains unknown how these signalling aggregates are resolved. Here we identify the mitochondria-resident E3 ligase, MARCH5, as a negative regulator of MAVS aggregates. March5(+/−) mice and MARCH5-deficient immune cells exhibit low viral replication and elevated type-I interferon responses to RNA viruses. MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. MARCH5, but not its RING mutant (MARCH5(H43W)), reduces the level of MAVS aggregates. MARCH5 transfers ubiquitin to Lys7 and Lys500 of MAVS and promotes its proteasome-mediated degradation. Our results indicate that MARCH5 modulates MAVS-mediated antiviral signalling, preventing excessive immune reactions.
Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4+ and CD8+ T-cell responses in the elderly positively correlates with response size
Authors: Chiu Yen-Ling , Sung Bo-Yi , Schneck Jonathan P , Lin Chung-Hao , Chuang Yi-Fang , Kern Florian , Pawelec Graham P , Wang George C 
Published: January 2023

Abstract
Cytomegalovirus (CMV) infection is one of the most common persistent viral infections in humans worldwide and is epidemiologically associated with many adverse health consequences during aging. Previous studies yielded conflicting results regarding whether large, CMV-specific T-cell expansions maintain their function during human aging. In the current study, we examined the in vitro CMV-pp65-reactive T-cell response by comprehensively studying five effector functions (i.e., interleukin-2, tumor necrosis factor-α, interferon-γ, perforin, and CD107a expression) in 76 seropositive individuals aged 70 years or older. Two data-driven, polyfunctionality panels (IL-2-associated and cytotoxicity-associated) derived from effector function co-expression patterns were used to analyze the results. We found that, CMV-pp65-reactive CD8+ and CD4+ T cells contained similar polyfunctional subsets, and the level of polyfunctionality was related to the size of antigen-specific response. In both CD8+ and CD4+ cells, polyfunctional cells with high cytotoxic potential accounted for a larger proportion of the total response as the total response size increased. Notably, a higher serum CMV-IgG level was positively associated with a larger T-cell response size and a higher level of cytotoxic polyfunctionality. These findings indicate that CMV-pp65-specific CD4+ and CD8+ T cell undergo simultaneous cytotoxic polyfunctionality maturation during aging.
Open chromatin landscapes of human CD8 T cell subsets reveal transcription factors associated with differentiation and aging
Authors: Zhang David 
Published: January 2023

Abstract
The epigenomic changes in differentiation and aging in T cells have broad impact on the efficacy of the adaptive immune system. Using the assay for transposase-accessible chromatin (ATAC-seq), we generated genome-wide chromatin accessibility maps in CD8 T cell subsets from age-segregated human donors. We find that distinct transcription factor families maintain the naïve and memory T cell states, including ETS and bZIP. In aging, we observe that differentiation-associated factors become more prominent. Additionally, a general shift in chromatin openness from promoters to enhancers is evident, with promoter-binding factors like NRF1 implicated as the drivers. Our results describe immune aging in T cells as the erosion of accessibility at promoters and predisposition toward a differentiated state.
FcγRIIIa (CD16a) drives the differentiation of peripheral human naive CD4+ T-cells
Authors: Chauhan Anil K , Moore Terry L , Chen Chen , Bi Ye 
Published: January 2023

Abstract
Activated human naïve CD4+ T-cells express FcγRIIIa receptors, which may serve as a checkpoint for immune homeostasis. A positive co-stimulation from FcγRIIIa (CD16a) will override the negative co-stimulation to drive immune expansion in autoimmunity. In an autoimmune background, FcγRIIIa via pSyk signal generated IFN-γhigh, TH17 and TFH populations. FcγRIIIa-pSyk signal up-regulated more than 80-fold toll-like receptor (TLR)3 and TLR8 proteins and enzymes that drive epigenetic modifications. FcγRIIIa-pSyk was observed both upon in vitro activation of naïve CD4+ T-cells and in vivo in CD4+ gated cells in SLE patients. Activated CD4+ T-cells expressing CD25, CD69 and CD98 also show FcγRIIIa-pSyk signaling. Cells with FcγRIIIa-pSyk signaling show ICOS and Bcl6 expression, markers of TFH. Adaptor and TLR interacting proteins BTK, HMGB1, HRAS, and MyD88 were upregulated. Labeled ICs that bound to FcγRIIIa also co-localize with HMGB1 and MyD88 in activated CD4+ T-cells. Western blots of IPs generated with anti-FcγRIIIa antibody show association of HMGB1 and MyD88 with FcγRIIIa. Three enzymes from epigenetic array ATF2, HAT6, and KAT6A showed several folds increase from FcγRIIIa engagement by ICs vs. CD28 co-signal.
Past literature from over three decades have suggested that CD4+ T-cells do not express Fc-receptors. Although, this may be true for quiescent normal CD4+ T-cells, activated CD4+ T-cells not only express FcγRIIIa but signal via Syk. FcγRIIIa mediated signal efficiently replaces CD28 co-signal and rescue naïve cells activated with sub-optimal CD3 ligation. FcγRIIIa will act as vehicle for DNA delivery to endosomes in T-cells. We describe a new role for FcγRIIIa in adaptive immunity mediated by CD4+ T-cell responses.
T cell up-regulation of CD127 is associated with reductions in the homeostatic set point of the peripheral T cell pool during malnourishment.
Authors: Gubbels Bupp Melanie R , Murphy Sarah , Patrick Kristin , Thoner Timothy , Edwards R. Whitney , Litvin Seth 
Published: January 2023

Abstract
The following study was undertaken to better understand the impact of short-term malnutrition on T cell homeostasis, with particular attention focused on the CD127/IL-7 signaling dynamic of peripheral T cells in mice. We report that the total number of peripheral naïve and memory CD4+ and CD8+ T cells notably declined after one week of mild malnourishment, a time period too short to be entirely due to malnutrition-induced thymic involution. Peripheral malnourished T cells expressed higher levels of the IL-7 receptor component, CD127, and were less sensitive to death-by-neglect as compared to control T cells. Adoptive transfer studies revealed that CD127 expression did not correlate with increased survival in vivo and that all naïve CD8+ T cells upregulated CD127, regardless of initial expression levels. Corticosterone levels were elevated in malnourished mice and this correlated in time with peripheral T cell up-regulation of CD127 and the diminishment of the peripheral T cell pool. Overall, these data suggest a model in which CD127 levels are up-regulated quickly during malnourishment, thereby increasing the scavenge rate of IL-7, and providing a mechanism to quickly adjust the total number of T cells during malnutrition.
Regulation of Regulatory B Cells by Th2 Cytokines
Authors: Taitano Sophina Horne , Lundy Steven K 
Published: January 2023

Abstract
Regulatory B cells (Breg) have emerged as important members of the immune regulatory network, particularly in the context of autoimmunity and tissue transplant. Previously we found that IL-5 supported the growth and functions of Breg cells, including production of IL-10 and FasL-mediated T cell killing. In contrast, IL-4 did not support regulatory B cells growth or function and instead antagonized the effects of IL-5. Signal transducer and activator of transcription-6 (STAT6) is the primary STAT activated by IL-4. We hypothesized IL-4 effects on B cells were mediated by STAT6, and that STAT6−/− mice would have more abundant and effective regulatory B cells. Flow cytometric analysis of naïve B cells from STAT6−/− and BALB/c wild-type mice indicated differences in some Breg phenotypes. Culture with CD40L, IL-5, and/or IL-4 stimulation were used to assess the IL-10 production, FasL mediated killing, and activated phenotypes. As anticipated, STAT6−/− B cells did not lose regulatory function when cultured with CD40L, IL-5, and IL-4. Interestingly, when BALB/c B cells were cultured with CD40L and IL-5 to expand regulatory B cells and then re-cultured in the presence of IL-4, regulatory functions were not affected. These results suggested the inhibitory effects of IL-4 on Breg cells is likely to be due to competition of other B cells in the culture rather than direct inhibition. To confirm these findings in vivo, STAT6−/− and control mice were immunized with OVA emulsified in IFA and their B cells were compared phenotypically and functionally. Our data suggest that regulatory B cell growth, IL-10 production, and FasL mediated killing may be supported by IL-5 and CD40L stimulation, and are not directly affected by IL-4 as previously thought.
Antigen presentation via intravascular extensions of renal DC is necessary for antigen-specific T Cell migration into the kidney
Authors: Yatim Karim , Gosto Minja , Humar Rishab , Williams Amanda L. , Oberbarnscheidt Martin H. 
Published: January 2023

Abstract
We have previously shown that CX3CR1+ renal DC sample antigen via intravascular processes in the context of systemic infection and immune complex disease. Here, we investigated the role of intravascular DC processes in antigen presentation and effector T cell migration to the kidney.
To investigate T cell migration, CFP-OVA E. coli and CD8+ DsRed+ OT-I effector T cells, pretreated with Pertussis toxin (PTX), were i.v. injected into CX3CR1gfp/+ mice 24h before 2P intravital microscopy (2PIM) of the kidney was performed.
OT-I T cells migrated into the kidney, with 2PIM showing prolonged (30 min) DC-T cell interactions. OT-I migration was significantly higher (2-fold) when OVA was present (CFP-OVA E. coli vs WT E.coli), demonstrating that migration of effector T cells was antigen-specific. To test if antigen presentation by DC was necessary to mediate migration of T cells, we used CD11c-YFP Kb−/− bone marrow chimeric recipients (hematopoietic cells lack H-2k(b), parenchymal cells express H-2k(b)). CFP-OVA E. coli injection into a CD11c YFP Kb−/− bone marrow chimeric mouse abrogated effector OT-I T cell migration into the renal tissue.
Our data demonstrate that migration of effector T cells in the setting of systemic infection is antigen-specific. In addition, antigen presentation by hematopoietic cells, most likely DC, is necessary to mediate antigen-specific effector T cell migration. H-2k(b) expression on parenchymal and endothelial cells does not mediate antigen-specific effector T cell migration. Our findings show that renal DC have two roles: immune surveillance by sampling and presenting antigen via intravascular processes, and guiding effector T cells to the site of antigen.
H. pylori infection promotes intestinal inflammation and colitis-associated colon cancer in mice with a lineage-restricted deletion of the Smad4 gene in T cells.
Authors: Kim Byung-Gyu , Choi Sung Hee Hee , Bagheri Nayer , Nedrud John , Letterio John 
Published: January 2023

Abstract
Recent data suggest a protective effect of Helicobacter pylori (H. pylori) infection in inflammatory bowel disease (IBD), but the mechanisms mediating this protective effect are poorly understood. We previously reported that selective deletion in T cells of the TGF-β signaling intermediate in mice, Smad4 (Smad4TKO mice) leads to spontaneous gastrointestinal inflammation which progresses to mucosal epithelia cancers. Thus we infected Smad4TKO mice with H. pylori SS1 and PMSS1. Smad4TKO mice developed thickened intestinal mucosa, epithelial hyperplasia, crypt abscesses, and abundant inflammatory cell infiltrates between 2 and 3 months post infection. Some mice also developed colonic adenocarcinoma while wild type (WT) infected mice exhibited no gross or histologic signs of colitis. Smad4TKO mice infected with H. pylori had a increase in the number of mucosal effector CD4+ T cells producing IFN-g and IL-17 and a decrease in the mucosal Foxp3+CD4+ T cells (Tregs) in vivo, compared to WT mice infected with H. pylori. We also observed enhanced epithelia expressing PD-L1 in colon of Smad4TKO mice with H. pylori infection. The colon epithelia of Smad4TKO mice with H. pylori infection exhibited an oncogenic signature with an increase in the expression of iNOS and p-STAT1. Mutations in Smad4 are found in large percentage of human Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HTT) patients who are at risk of developing both adolescent and adult colon cancer. Our results raise the intriguing possibility that H. pylori infection could be a co-factor in the development of colon cancer by JPS/HTT patients.
MAdCAM as a potential biomarker of HIV-induced inflammation
Authors: Andrews Omozusi E , Van Ryk Donald , Ansari Aftab , Cicala Claudia , Fauci Anthony , Arthos James 
Published: January 2023

Abstract
HIV causes a slowly progressive immunodeficiency disease via depletion of helper T cells and other immune cells, eventually resulting in AIDS. Currently, no effective vaccine exists for HIV. Acute HIV infection is associated with viral replication in, and of destruction of gut tissues. A key subset of gut-homing immune cells, CD4+ T cells expressing the integrin receptor α4β7, are highly susceptible to HIV infection. α4β7+/CD4+T cells gain entry to gut tissues by binding to MAdCAM, a receptor that is expressed on the surface of endothelial cells that line gut-associated lymphoid tissues (GALT). In a recent study of rhesus macaques infected with SIV we observed dramatic increases in levels of soluble MAdCAM in the serum shortly after infection. The presence of soluble MAdCAM in serum, correlated with viral replication in GALT, and suggested that MAdCAM was shed from the surface of endothelial cells in response to immune activation and inflammation of gut tissues. To investigate the regulation and functionality of MAdCAM, we generated distinct recombinant Rhesus macaque MAdCAM proteins including both soluble and membrane bound forms. Plate bound assays demonstrated that soluble rhesus MAdCAM can function as a T cell co-stimulatory signal. Human CD4+ T cells substantially proliferated in the presence of soluble rhesus MAdCAM proteins and proliferation diminished in the presence of the anti-α4β7 (ACT1) antibody. Importantly, since HIV infects GALT, which contains the majority of immune cells, the study of MAdCAM-α4β7 signaling and mechanisms of MAdCAM shedding may provide insight on potential mucosal-based therapies for treating HIV and serve as a biomarker of HIV-induced gut inflammation, respectively.
Intestinal inflammation drives differentiation of tissue-resident memory CD8+ T cell populations with enhanced migratory ability
Authors: Bergsbaken Tessa , Fink Pamela J 
Published: January 2023

Abstract
Tissue-resident memory (TRM) CD8+ T cells represent a distinct population of memory T cells that are maintained independently of the circulation and are positioned to respond rapidly to reinfection of the tissue. Using intestinal infection with the bacterial pathogen Yersinia pseudotuberculosis, we determined that CXCR3-mediated recruitment to areas of inflammation during bacterial colonization drives differentiation of a CD103− subset of lamina propria (LP) CD8+ TRM cells. However, the inflammatory cytokines that regulate the development of this subset remain unidentified. Ex vivo cytokine stimulation of Yersinia-primed CD8+ effector T cells identified several cytokines capable of preventing CD103 upregulation by TGF-beta, including IFN-beta and IL-12. Yersinia infection resulted in induction of IL-12 and IFN-beta in infected macrophages both in vitro and in proinflammatory microenvironments in the intestinal tissue. Eliminating IFN-beta signaling in T cells resulted in the preferential development of CD103+ T cells during infection, indicating type I interferon plays a role in the differentiation of the CD103− LP TRM population. Ex vivo migration assays indicated CD103− LP TRM cells are able to migrate more readily than CD103+ cells; these populations also display distinct chemokine receptor profiles, supporting differential migration of LP TRM populations in response to secondary challenge. These studies identify inflammatory cytokines encountered in the intestinal tissue that can dictate the phenotype and function of CD8+ TRM cells.
Colonic intraepithelial lymphocytes produce IL-6 in response to resident bacteria to modulate epithelial barrier function
Authors: Kuhn Kristi , Regner Emilie H. , Mehta Gaurav , Hendrickson Jason D. , Whitney Alyssa K. , Campbell Eric L. , Ohri Neha , Colgan Sean P. 
Published: January 2023

Abstract
Interactions between the microbiota and distal gut are important for the maintenance of a healthy immune system. Dysbiosis of colon bacteria has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine, function to maintain epithelial homeostasis. We hypothesized that IELs of the colon modulate epithelial barrier function through the liberation of cytokines stimulated by interactions with resident bacteria. Our data demonstrate that IL-6 is a major cytokine secreted by colonic IELs in a microbe-dependent fashion. We identify Alistipes species of the phylum Bacteroidetes as candidates to recruit IELs and stimulate their IL-6 secretion. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6−/− and antibiotic-treated mice were noted to have increased paracellular permeability and closer interaction with luminal bacteria. IL-6 was found to signal in colonic epithelial cells and resulted in increased epithelial barrier integrity and claudin1 expression in model epithelia. Therefore, we conclude that the host microbiota provides a homeostatic role for epithelial barrier function through regulation of IEL derived IL-6.
Vitamin D deficiency results in fewer innate lymphoid cells and severe infection with Citrobacter rodentium.
Authors: LIN YANG-DING , Cantorna Margherita T 
Published: January 2023

Abstract
Vitamin D deficiency results in severe experimental inflammatory bowel disease. We investigated the role of vitamin D following an infectious model of inflammation in the gut following Citrobacter rodentium infection. Vitamin D sufficient (D+) and vitamin D deficient (D−) wild-type (WT) and Cyp27B1 knock-out (CypKO) mice, which lack the enzyme to produce the high affinity ligand, 1,25(OH)2D (1,25D), were infected. In the absence of 1,25D, the low affinity vitamin D ligand (25(OH)D) accumulates in CypKO mice and can replace 1,25D. Therefore it was not surprising that D+ WT and D+ CypKO cleared C. rodentium with identical kinetics. D− WT mice cleared C. rodentium slower than D+ mice and D− CypKO mice developed a lethal infection. Infected D− CypKO and D− WT mice had increased colonic inflammation, systemic bacterial dissemination, but only D− CypKO mice died following infection. Increased colonic IL-17 mRNA in D− versus D+ mice at d14 post-infection was perhaps too late to protect the D− mice from C. rodentium. Innate lymphoid cells (ILCs) are critical sources of early IL-17 and IL-22 that are essential for clearance of C. rodentium. Uninfected D− mice had reduced ILCs in the gut and decreased ILC-derived IL-17 and IL-22 in the small intestine, which is the site of early colonization of C. rodentium. Vitamin D deficiency resulted in delayed clearance of C. rodenitum that was associated with reduced ILC produced early IL-17 and IL-22, more inflammation and IL-17 at the peak of infection. The data suggests that vitamin D may be an important regulator of early cytokine production by ILC in the gut and therefore protection from enteric infection.
T-bet-independent TH1 immunity to Toxoplasma gondii drives intestinal immunopathological response
Authors: Lopez-Yglesias Americo H , Burger Elise , Yarovinsky Felix 
Published: January 2023

Abstract
Coordinated production of IFN-γ by innate and adaptive immune cells is central for host defense, but can also trigger immunopathology. The investigation of lymphoid cell specific contribution to the IFN-γ-mediated intestinal pathology during Toxoplasma gondii (T. gondii) infection identified that CD4+ T cells but not group 1 innate lymphoid cells (ILC1s) are responsible for IFN-γ-dependent Paneth cell death, inflammation, and bacterial dysbiosis. We identified that lack of T-bet, the lineage-defining transcription factor for ILC1s and a maturation factor for intraepithelial lymphocytes had no detectable effect on T. gondii induced intestinal inflammation, ruling out contribution of these cells in the parasite-induced immunopathology. Instead, we show that T-bet deficient CD4+ T helper 1 (TH1) cells are necessary and fully sufficient for the T. gondii triggered acute ileitis. These results revealed that T-bet-independent TH1 effector cells are functional mediators of type I immunopathological response during acute gastrointestinal infection.