bluuebunny/crossref_metadata_2025_split huggingface dataset:
A joint role for IL-2 and IL-15 in the differentiation and survival of short-lived effector and effector memory CD8+ T cells (83.2)
Authors: Williams Matthew A , Mitchell Diana M. , Ravkov Eugene V 
Published: January 2023

Abstract
Interleukin-2 (IL-2) plays a central role in the differentiation of functionally competent CD8+ memory T cells. In this study, we found that in the absence of IL-2 signals, the differentiation of short-lived CD8+ effector T cells and tissue-residing effector memory CD8+ T cells in response to acute infection was greatly impaired. Due to their shared signaling apparatus, we explored the hypothesis that IL-15 signals might also contribute to the differentiation and survival of these populations. In line with this hypothesis, we observed an additional impairment in the differentiation and persistence of short-lived effector/effector memory cells in the spleen when both IL-2 and IL-15 signals were absent. Furthermore, in the absence of IL-2 and IL-15 signals this population disappeared completely by day 15. In contrast, joint inhibition of IL-2 and IL-15 signals had no further impact on the differentiation of tissue-residing CD8+ effector memory T cells. While IL-2 and IL-15 contributed to the differentiation of short-lived effector cells during the primary response, IL-15 continued to play a mandatory role in the survival of these cells during contraction and memory. These findings delineate a joint role for IL-15 and IL-2 in the differentiation of short-lived CD8+ effector cells but point to unique roles for IL-15 and IL-2 in promoting the survival of short-lived effector/effector memory cells in the spleen and the differentiation of tissue-residing effector memory cells, respectively.
Exploring Myths of CD8+ T Cell Contraction (83.22)
Authors: Prlic Martin , Bevan Michael J 
Published: January 2023

Abstract
A small fraction of the CD8 T cell effector population that responds to an infection progresses through the contraction phase to the memory stage. The factors regulating the extent of contraction are poorly understood. In previous experiments, parameters such as inflammation, antigen presentation, etc. were modified during the priming/expansion phase and the consequences of these changes were monitored in the contraction phase. A major caveat of these studies is that the experimental setup did not allow examination of the contraction phase without altering the priming phase first. We developed a system based on bim-/- CD8 T cells that overcomes this confounding problem. Competition for limited resources has been widely postulated to be the cause of cell death during the contraction phase, but our data show that competition does not affect contraction kinetics. All effector cells present at the peak of the response have the potential to become bona fide memory cells, thus excluding selection based on functionality. We propose that cell death during contraction is the default pathway for an effector cell and identify a set of genes that may be key regulators for surviving contraction.
This work was supported by the Howard Hughes Medical Institute and National Institutes of Health Grant AI-19335 (to M.J.B.). M.P. is a fellow of The Leukemia & Lymphoma Society. The authors have no conflicting financial interests.
Suppression of CD8 T cell survival by the synthetic adjuvant poly (I:C) at low dosage (83.3)
Authors: Ngoi Soo Mun , Vella Anthony T 
Published: January 2023

Abstract
The synthetic double-stranded RNA (dsRNA) poly I:C is commonly used as an adjuvant to boost CD8 T cell functions through type I IFN production but is also effective at suppressing disease development in certain autoimmunity models. It is unclear how a single adjuvant achieves two distinct immunoregulatory roles. By utilizing the transgenic T cell OTI adoptive transfer model, we found that low dose poly I:C suppresses costimulation-enhanced CD8 T cell survival. Perhaps surprisingly, early expansion and effector differentiation were not significantly impacted. Reduction in CD8 T cell survival was rescued by increasing the poly I:C dosage and is dependent on the precursor frequency of antigen-specific CD8 T cells. We hypothesize that the opposing effects of poly I:C on CD8 T cells at low versus high doses depend on differential activation of multiple dsRNA receptors. Compared to the intracellular dsRNA receptors such as MDA5 and RIG-I, TLR3 may have better access to poly I:C in soluble form due to its strategic location in the endosomal compartment. Hence we postulate that TLR3 is responsible for suppression of CD8 T cell survival when low dose poly I:C is administered. Indeed, a minor subset of splenic B cells that express CD5 and CD21 surface markers produce IL-10 in response to poly I:C. Interleukin-10 synthesis was inhibited in TLR3-/- B cells, although these cells were capable of producing IL-10 in response to PMA and ionomycin. The relationship of IL-10 and reduced T cell survival is being explored, as is the anatomical location of the CD5+CD21+ B cells. Consistent with other reports on the immunoregulatory role of IL-10-producing B cells on adaptive immunity, our findings further suggest the feasibility of fine-tuning such regulatory balance by altering the dosage of TLR ligands.
Cell division predicts CD62L expression in vivo (83.6)
Authors: Davenport Miles P , Schlub Timothy , Sabel Jaime L , Harty John T , Badovinac Vladimir P 
Published: January 2023

Abstract
Naïve CD8+ T cells express a predominantly CD62Lhigh phenotype, but CD62L expression is rapidly lost during the effector phase of the immune response and only slowly regained during the memory phase. We used adoptive transfer of TCR-transgenic T cells followed by Listeria infection to study the dynamics of cell division and differentiation in vivo. Adoptive transfer of larger quantities (400 000) of naïve TCR-transgenic T cells leads to diminished T cell growth following infection and a higher proportion of cells remaining CD62Lhigh than populations derived from adoptive transfer populations of smaller quantities (3200 naïve TCR-tg T cells). This suggests a process of 'division-linked differentiation', where a proportion of cells change phenotype (in this case CD62Lhigh =&gt; CD62Llow) upon division. A simple model of division-linked CD62L differentiation where 20% of CD62Lhigh cells differentiate to become CD62Llow on each division accurately predicts the phenotype of cells during acute infection. By contrast, expression of CD127 did not conform to this simple pattern of differentiation. These results suggests that CD62Lhigh and CD62Llow cells arise from the same precursors, and CD62Llow cells are formed from the CD62Lhigh population by a process of progressive, division-linked differentiation.
Phosphoinositide dependent kinase 1 (PDK1) maintains T-cell metabolism during proliferative stress (84.20)
Authors: Macintyre Andrew N. , Kelly April P. , Cantrell Doreen A. 
Published: January 2023

Abstract
Phosphoinositide dependent kinase 1 (PDK1) is a serine/threonine kinase that phosphorylates and activates protein kinase B (PKB/Akt) and the p90 ribosomal S6 kinase (RSK). Naïve T-cells lacking PDK1 are viable in a thymic environment, show normal ex-vivo survival responses to IL7 and can migrate normally to secondary lymphoid tissue. However, when induced to proliferate by antigen receptor triggering or a lymphopenic environment PDK1 deleted naïve T-cells are unable to survive. Activated CD8+ effector T-cells lacking PDK1 suffer gross metabolic defects with reduced rates of aerobic glycolysis, decreased glucose uptake and abnormal lipid metabolism, and cannot sustain proliferation or survival. A T-cell's requirement for PDK1 as a driver of metabolism is therefore limited to periods of proliferative stress. Strikingly, in peripheral T cells the ability of PDK1 to sustain T cell metabolism is not mediated solely by Akt but includes a critical synergistic contribution by RSK kinases. PDK1 thus has a key role in controlling energy metabolism and the survival of proliferating T cells, but distinct PDK1 independent signalling pathways regulate naïve T cell survival.
Funded by the Wellcome Trust.
Microarray analysis of genes induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in thymic progenitor cell populations prior to thymic atrophy (84.3)
Authors: Silverstone Allen E , Laiosa Michael D , Lai Zhi-wei , Middleton Frank A , Mills Jeffrey H , Singh Kameshwar P , Gasiewicz Thomas A 
Published: January 2023

Abstract
TCDD activates the Aryl Hydrocarbon Receptor (AhR), a basic helix-loop-helix transcription factor, and causes thymic atrophy in all species examined. We have previously shown [Laiosa, et. al. J. Immunol. (2004) 171 4582-91] that the earliest detectable effect associated with TCDD induced thymic atrophy was a decline in the percentage of S phase cells in the CD3-CD4-CD8- triple negative (TN) intrathymic progenitor 3 and 4 stages within 9-12 hours of treatment, prior to any detectable reductions in thymocyte cell number. We also demonstrated that this effect was strictly by activation of the AhR in the developing lymphocytes. We now show, using microarray analysis, that 108 distinct genes are affected in the TN1-4 thymic progenitor stages 6 and 12 hours after TCDD treatment. While most of these genes have specific AhR recognition sequences, only 7 genes were altered exclusively in the TN3 and 4 stages. Interestingly, all 7 of these genes demonstrated a decrease in expression. These 7 genes represent novel targets of AhR transcriptional activity in the developing immune system. Future work will test the hypothesis that these 7 genes play a critical role for thymocyte cell cycle regulation and proliferation following TCRβ selection.
Funded by 5RO1- ES04862 (TAG) and Hendricks Fund (Syracuse University).
A haplotype of the HLA-DRA gene promoter region was associated with susceptibility to gastric cancer in a Korean population (88.1)
Authors: Kwack KyuBum , Pyun Jung-A , Kim Kyoung-Yeon , Lee Seung Ku , Oh Ah Reum , Kim Min-Ho , Kang HyunJun , Won SungSik , Lee Kwang-Jae , Cho Sung Won , Kim Jeong-Geun 
Published: January 2023

Abstract
Gastric cancer, the second leading cause of mortality by cancer in the world, shows particularly high incidence and mortality in Korea. To screen the causative genes or loci that control the transition from gastritis to gastric cancer, whole genome approach was applied using Illumina's 510S SNP chip technology. One of the interesting associated genes, HLA-DRA1 was investigated. HLA-DRA gene is very limited in polymorphism compared to the highly polymorphic HLA-DRB1, 3, 4, and 5 loci. HLA-DR alpha protein has roles as a non-polymorphic partner for HLA DR-beta for transport and surface expression as a functional HLA-class II protein. The expression level of the HLA-DR alpha/beta on the cell surface may be controlled by the transcriptional level of the HLA-DR alpha. To test this hypothesis, we tested susceptibility to gastric cancer compared to gastritis in terms of SNPs, haplotypes, and diplotypes covering the HLA-DRA promoter region. To find causative SNP(s), the whole linkage disequilibrium (LD) region of the significant haplotype using more than 20 Koreans were sequenced. We found that a diplotype composed of significantly associated SNPs and a haplotype was associated with susceptibility to gastric cancer significantly. These data suggested that the expression level of HLA-DRA might control the HLA-DR protein levels on the cell surface.
Immune contexture and cancer prognosis (88.28)
Authors: GALON Jerome , TOSOLINI Marie , KIRILOVSKY Amos , CAMUS Matthieu , MLECNIK Bernhard , BINDEA Gabriela , TRAJANOSKI Zlatko , BRUNEVAL Patrick , BERGER Anne , FRIDMAN Wolf-Herman , PAGES Franck 
Published: January 2023

Abstract
To date the anatomic extent of tumor (TNM classifications) has been by far the most important factors to predict the prognosis of colorectal cancer patients. However, the impact of immune responses and tumor escape on patient prognosis in human cancer is poorly understood.
We showed that tumors from human colorectal cancer with a high density of infiltrating memory and effector memory T-cells (TEM) are less likely to disseminate to lymphovascular and perineural structures and to regional lymph-nodes. We showed that the combination of immune parameters associating the nature, the density, the functional orientation and the location of immune cells within the tumor was essential to accurately define the impact of the local host immune reaction on patients prognosis. We proposed to define these immune criteria as "immune contexture". Investigation of the CRC primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response. We described four major immune coordination profiles within CRC primary tumors depending on the balance between tumor escape and immune coordination.
In conclusion, the density and the immune-cell location within tumor regions had a prognostic value that was superior of those of the TNM classifications. Tumor invasion was dependent on the host immune reaction.
The role of IL-6 and IL-23 in colitis associated cancer (88.30)
Authors: Grivennikov Sergei , Mucida Daniel , Terzic Janos , Rose-John Stefan , Eckmann Lars , Cheroutre Hilde , Karin Michael 
Published: January 2023

Abstract
Colitis associated cancer (CAC) is the most serious complication of inflammatory bowel diseases (IBD). Pro-inflammatory cytokines regulated by NF-B were suggested to regulate pre-neoplastic growth during CAC tumorigenesis. We tried to dissect the roles of individual cytokines in CAC tumorigenesis. Using genetic tools and a mouse model of azoxymethane/dextrane sodium sulfate induced CAC we demonstrate that IL-6 and IL-23 are critical tumor promoters during early CAC tumorigenesis. IL-6 and IL-23 act on cells of innate and adaptive immunity, particularly on T cells. Additionally, these cytokines have direct and indirect effects on intestinal epithelial (IEC) and neoplastic cells. These effects are mediated by transcription factor STAT3, whose IEC-specific ablation reduces CAC tumorigenicity. We conclude that IL-6 and IL-23 regulate multiple stages of colonic tumorigenesis, particularly tumor initiation and tumor growth. Selective inhibition of these cytokines may be beneficial for treatment and prevention of CAC.
Supported by RFA from Crohn`s and Colitis Foundation of America (CCFA #1762) to S.G. and by grants from the NIH and a Jeannik M. Littlefield-AACR grant in metastatic colon cancer to M.K.
A short term assay for evaluating the functional potential of isolated human regulatory T cells (89.14)
Authors: Ruitenberg Joyce J. , Ghanekar Smita A. 
Published: January 2023

Abstract
Naturally occurring human regulatory T cells (Tregs) are able to actively suppress auto reactive immune responses. Phenotypically, they are characterized as CD4+, CD25++, CD127- and FoxP3+. Determining whether Tregs can suppress the antigen-specific cytokine expression of autologous PBMC would provide useful insight into the functional abilities of these cells. Long term assays such as proliferation are routinely used to analyze the functional capability of Tregs, but for practical reasons, a short term intracellular cytokine staining (ICS) assay would seem to be a more valuable tool for assessing the potency of Treg. In this study, we have demonstrated that highly purified and in vitro expanded Treg are capable of suppressing T-cell specific cytokine responses in 7 hr ICS assays. Treg were purified from healthy donor PBMC by sorting the CD4+CD25++CD127dim/- cells with a BD FACSAria(tm) flow cytometer. The functional ability of the highly purified Treg was evaluated either after activation for approximately 20 hours, or after in vitro expansion for 12 to 14 days. Activation of PBMC with SEB and/or CD3/CD28 results in the expression of inflammatory cytokines (IFNγ, and TNFα) by CD4+ and CD8+ T cells. The data from this study indicate that the addition of CD4+CD25++ cultured Treg to the ICS assay of autologous PBMC results in suppression (i. e. reduced frequency of) cytokine expressing T cells. There was no correlation between the frequency of FoxP3+ Treg and % suppression of cytokine+ effector cells. Since the intracellular T-cell cytokine expression assay has been validated extensively, this short-term assay could reduce the time needed to qualify Treg for immunotherapy.
Expansion of Tregs in Aged, but not Young Mice following Influenza Infection (89.7)
Authors: Williams-Bey Yolanda , Jiang Jiu , Murasko Donna M 
Published: January 2023

Abstract
The increase mortality and morbidity commonly seen with aging is believed to be in part due to a negatively altered immune response. The role of regulatory T cells (Tregs) in relation to reduced immune response in aging was investigated. In this study we compared the function and phenotype of Tregs isolated from young (4-6 mos) and aged (18-22mos) C57bl/6 mice. Both young and aged Tregs significantly reduced the activation and expansion of specific CD8 T cells, however there was no difference in the level of suppression induced by young versus aged Tregs. There was a strong negative correlation between Treg percentage and CD8 T cell activation. To further establish the negative correlation between specific CD8 T cell expansion and Tregs, mice were infected intravenously (i.v.) with influenza virus (PR8 strain) and sacrificed 5, 7 and 10 days post infection. While adult mice produce a strong response to influenza aged mice had a reduced and delayed response. Aged mice demonstrated a significant increase in the proportion of Treg over the course of infection, while young mice demonstrated no such change, maintaining a consistent percentage of Tregs. Our results suggest the increase in Tregs following influenza infection interfere with specific CD8 T cell expansion and function. These studies demonstrate the further need to assess the role of Tregs in the decreased immune response in elderly individuals.
Characterization of the in vivo function of the leukocyte-associated Ig-like receptor (LAIR)-1 (90.27)
Authors: tang xiaobin , Esteso Tornero Gloria , Coligan John E , borrego francisco 
Published: January 2023

Abstract
Leukocyte-associated Ig-like receptor-1 (LAIR-1) is an immunoreceptor tyrosine based inhibitory motif (ITIM) containing receptor. The ligand for LAIR-1 is the GPO repeats present in all collagens. Cross-linking of LAIR-1 in vitro with antibodies or collagens delivers an inhibitory signal that is able to down-regulate TCR mediated signals. To study the in vivo function of LAIR-1, we have generated LAIR-1-/- and LAIR-1flox/flox mice on a C57Bl/6 background. LAIR-1-/- mice appear to be healthy and fertile, and have normal longevity. LAIR-1-/- mice show a slight increase in the percentage of splenic B cells, along with a decrease in T cells. Since LAIR-1+/+ and LAIR-1-/- T cells traffic equally to peripheral lymphoid organs, this is probably not the result of abnormal T lymphocyte trafficking. When OT-II LAIR-1-/- CD4 T cells are cultured with APC loaded with OT-II OVA peptide, they proliferate significantly less than OT-II LAIR-1+/+ CD4 T cells. However, in vivo, OT-II LAIR-1-/- CD4 T cells proliferate similarly to OT-II LAIR-1+/+ CD4 T cells in response to challenge with albumin. Without any stimulation, LAIR-1-/- mice have lower levels of IgG3 and IgG1 in the serum. In response to T-dependent immunization with TNP-OVA in alum, LAIR-1-/- switch less efficiently to IgG2a and IgG2b production, while switching to IgG1 is not affected. In response to T-independent immunization with TNP-LPS and TNP-ficoll, no significant differences in immunoglobulin levels were observed between LAIR-1-/- and LAIR-1+/+ mice. Several mouse disease models, including those for experimental autoimmune encephalomyelitis (EAE), inflammatory bowel disease (IBD) and hapten induced contact hypersensitivity (CHS), were utilized to try to determine how LAIR-1 functions in vivo. No differences were observed, except that preliminary results show LAIR-1-/- mice are more susceptible to CHS.
Regulation of T cell responses by a distinct subset of resident splenic macrophages (90.3)
Authors: Kurotaki Daisuke , Morimoto Junko , Kanayama Masashi , Uede Toshimitsu 
Published: January 2023

Abstract
The balance between immune activation and tolerance must be regulated to maintain immune homeostasis. It has been well demonstrated that dendritic cells are critical regulators to maintain such balance. Tissue macrophages (Mφs) constitute the major cellular subsets of antigen presenting cells within body, however, it is poorly understood what kind of tissue resident macrophages is involved in the regulation of immune homeostasis in the peripheral lymphoid tissues. Here, we found that splenic Mφs could be divided into two subsets due to α9 integrin expression (F4/80intMac-1hiα9- and F4/80hiMac-1lowα9+). F4/80intMac-1hiα9- Mφ spontaneously secreted IL-6 and IL-12p40 and induced robust proliferation and differentiation of naive CD4+ T cells. These characteristics were met with the features of conventional splenic Mφ (cMφ). Mφs expressing α9 integrin (α9Mφs) were mainly localized in the red pulp. Unlike cMφs, α9Mφs expressed TGF-β and inhibited T cell proliferation by a mechanism partially dependent on TGF-β. Furthermore, α9Mφs were capable of inducing the differentiation of naive CD4+ T cells into Foxp3+ regulatory T cells via TGF-β. These results suggest that these distinct two Mφ subsets reciprocally control T cell immune responses in the spleen.
Foxp3 is expressed in LPS activated mouse microglial and modulates inflammatory responses. (92.12)
Authors: Chung Hwan-Suck , Lee Jun-Ho , Kim Hyunseong , Shin Min-Kyu , Hong Moo-Chang , Kim Yangseok , Bae Hyunsu 
Published: January 2023

Abstract
The starting point of this study was the serendipitous observation that forkhead box P3 (FOXP3) gene was up-regulated over 3 times in the LPS activated BV-2 microglial cells at 0.5h, 1, 3 and 6h in previous microarray. We confirmed that FOXP3 was expressed in the LPS activated mouse microglial by real time PCR and RT-PCR. Using FOXP3 mutant mouse (Scurfy), Scurfy microglial were released higher levels of CXCL10 and monocyte chemotactic protein 1 (MCP-1) by LPS treatment compared with wild type microglia. However, IL-6 and IL-1¥â in LPS activated scurfy microglia were same levels compared with wild type microglial. Scurfy microglial increased nitric oxide (NO) and Reactive oxygen species (ROS) generation by LPS treatment. These results suggest that FOXP3 may contribute to the suppression of CXCL10 and MCP-1 and to the decrease of NO and ROS in the LPS activated mouse microglial cells.