bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Function of Cancer-Induced Myeloid-Derived Cells (88.25)
Authors: Shin Tahiro , Tomihara Kei , Guo Miao , Zhang Bin , Curiel Tyler 
Published: January 2023

Abstract
Cancer is one of the most common life-threatening diseases, particularly in developed countries, and causes more than one third of all human deaths every year. The effects of standard treatments are still far from satisfactory. Thus, immunotherapies have been under investigation. The greatest merit of immunotherapy is its specificity, compared to non-specific standard treatments. However, one of the most important issues impeding cancer immunotherapy is the recruitment of the immune suppressor cells by cancer cells in the cancer microenvironment. These immune suppressors, represented by regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs), efficiently attenuate the CTL activities against cancer. By using the mouse ovarian cancer cell line, we have found that a large population of the CD11b+ and Gr-1+ cells instead of Tregs accumulated in ascites and the spleen. CD11b and Gr-1 are the typical markers for MDSCs, for instance, induced by the subcutaneous injection of mouse thymoma cell line. They were well characterized with its strong suppressive property and consist of heterogeneous population. However, the CD11b+ and Gr-1+ cells in ascites induced by the mouse ovarian cancer cell line were not suppressive and highly homogeneous population of granulocyte-like cells. We investigated the detail function of this population comparing with it of MDSCs.
Rapid change of PO2 promoted dendritic cells to induce a strong Th1 cell immune response with decreased Foxp3+Tregs (89.11)
Authors: Liu Chunmei , Wang Qun , Liu Fengming , Zhang Lining 
Published: January 2023

Abstract
Ischemia-reperfusion injury (IRI) can be found in transplantation and other ischemic syndromes in multiple organ systems including kindey, brain, heart and liver, this pathogenesis of IRI is complex and incompletely understood. It has been suggested that reoxygenation after hypoxia is a crucial mechanism mediating organ injury in IRI. Well, dendritic cells (DCs), the critical immune cells linking innate and adaptive immunity, are often exposed to various oxygen tensions under physiological and pathological conditions, such as ischemia-reperfusion. However, the effects of various oxygen tensions on DCs remain unclear. In this study, we showed that hypoxia-differentiated DCs expressed lower levels of MHC-|| molecule, co-stimulatory molecules (CD80, CD86) and pro-inflammatory cytokines (IL-1 β, IL-6, TNF-α and IL-12), but higher levels of immunoregulatory cytokine transforming growth factor-beta (TGF-b) than did normoxia-differentiated DCs. However, reoxygenation of the hypoxia-differentiated DCs dramatically upregulateed the aforementioned molecules leading to a mature phenotype. Significantly, these reoxygenated DCs induced syngeneic or allogeneic naïve CD4+ T cells to differentiate into Th1 effector cells. The generation of CD4+CD25+Foxp3+ regulatory T cells (Treg cells) induced by reoxygenated DCs was however down-regulated. These data indicate that hypoxic microenvironment suppresses the maturation and function of murine DCs. Re-exposure of the hypoxia-differentiated DCs to sutured oxygen however results in complete recovery of their mature phenotype and function and drives them to initiate Th1 cell differentiation, suggesting DCs play a critical role in inflammation in ischemia-reperfusion injury (IRI).
The ratio of Th1 /Treg or Th17/Treg is more important in the onset of acute coronary syndrome (89.2)
Authors: zhang lining , Zhu Faliang , Ma Tian , Gao Qi 
Published: January 2023

Abstract
Considerable evidence supports that CD4+ T lymphocyte, a highly heterogenous subset including Th1, Th2, Th17 and Treg, is the major lineage of T lymphocytes that involve in atherosclerosis, a chronic inflammatory disease of artery wall. Some reports show that Th1, Th17 and Treg may play a role in the plaque destabilization of atherosclerosis. However, the status and significance of Th1, Th17 and Treg in same patient remains largely unknown. In present study, we detected percentage of Treg, Th1 and Th17, related cytokines ( IFN-γ , IL17 and TGF-β ) and analyzed the ratio of these three subsets in same patient with acute coronary syndrome (ACS). Although increased Th1 or Th17 and decreased Tregs revealed statistical difference in group of patients with acute cortical syndrome compared with group of healthy individuals, percentage of Treg or Th17 or Th1 also did not show significant change in some patients. Our results further showed that the increased ratio of Th1/Treg and Th1+Th17/Treg in every patient with ACS. The similar results were found in apolipoprotein E-deficient mice with atherosclerotic plaque. Our data suggests that imbalance of effective CD4 subsets (Th1 and Th17) and inhibitory T subset ( Tregs) was more important in the onset of acute coronary syndrome.
Tyrosine phosphatase SHP-1 negatively regulates the suppressive potential of CD4+CD25+Foxp3+ regulatory T cells (89.26)
Authors: Iype Tessy , Sankarshanan Mohan , Mauldin Ileana , Lorenz Ulrike M 
Published: January 2023

Abstract
CD4+CD25+Foxp3+ regulatory T (Treg) cells are well recognized as mediators of peripheral immune tolerance. However, their function remains poorly understood at the molecular and mechanistic level. We have previously shown that mice, which are deficient in the protein tyrosine phosphatase SHP-1 ('motheaten' or me/me mice), have increased numbers of Treg cells. Since SHP-1 is a negative regulator of TCR-mediated signaling in conventional T cell, we investigated whether SHP-1 also plays a regulatory role in Treg cells.
A comparison of the suppressive activities demonstrated that Treg cells derived from me/me or me/+ mice suppressed lymphocyte proliferation in vitro more efficiently than Treg cells from wild type mice indicating that SHP-1 is a negative regulator of Treg cell-mediated suppression. Since based on micro array analyses, the differences in suppressive activities are not due to developmental disparities, our data suggest that SHP-1 directly regulates the suppressive activity of Treg cells. To gain a better mechanistic understanding of Treg cell-mediated suppression, flow cytometric and in particular ImageStream100 (Amnis) analyses were performed. These studies showed that in the absence of SHP-1, Treg cells express different levels of a number of surface and intracellular molecules. Moreover, SHP-1 deficiency promoted increased conjugate formation between Treg cells and antigen presenting cells as visualized by ImageStream100. Conjugate formation with SHP-1-deficient Treg cells caused a more efficient down-modulation of the co-stimulatory molecules CD80/CD86 on the dendritic cells. Taken together, our data indicate that SHP-1 regulates the function and activation status of Treg cells and that under conditions of SHP-1 deficiency, Treg cells become more potent.
Source: NIH, RO1 AI 048672
Regulation of T cell specific IL-10 production by non-IL-10 expressing T cell subset (89.32)
Authors: Stoyanoff Korynn , Blum Arthur , Hang Long , Setiawan Tommy , Leung John , Weinstock Joel 
Published: January 2023

Abstract
Intro: IL10 is an anti-inflammatory cytokine, important for the regulation of immune responses including the modulation of intestinal inflammation. Induction of IL10 production is well studied, but little is known about inhibition of its production, which was the topic of this study. Method: Reporter mice, whose cells concurrently express IL10 and EGFP were used. Unfractionated Lamina propria mononuclear (LPMC) or Spleen (Sp) cells were cultured for 24hrs with aCD3 stimulation and then stained and sorted into IL10+Thy+, IL10-Thy+, and IL10-Thy- populations. IL10+Thy+ T cells were cultured alone or in combination with IL-10- cells for 48hrs. Supernatants were analyzed for IL10 production by ELISA. Results: IL10+Thy+ LPMC or Sp cells produce high levels of IL10 when cultured alone (0.614 + 0.156 ng/ml, 15K Sp cells, N=3). Coculture with IL10-Thy+ cells (45K) led to significant inhibition of IL10 production (0.129 + 0.05 ng/ml, p=0.018, N=3 for Sp, 79.06% reduction). Lesser inhibition was seen with IL10-Thy- coculture. Inhibition appears to be CD8+ T cell-mediated. Reduced IL10 production was not due to IL10+ T cell death. Discussion: We have identified a population of IL10- T cells in the gut and Sp with novel inhibitory effects on IL10 production by T cells. These cells may maintain the balance between pro- and anti-inflammatory immune responses through mechanisms previously not described . (DK38327, 058755, 034928)
A single scurfy T cell-derived TCR is sufficient to induce multi-organ autoimmune disease (89.37)
Authors: Killebrew Justin R , Perdue Nikole , Campbell Daniel J 
Published: January 2023

Abstract
While the majority of T cells expressing self-reactive T cell receptors (TCRs) are eliminated in the thymus during development, a fraction emerge into periphery. We have created the SFZ70 TCR transgenic mouse to better understand the in vivo behavior of these peripheral auto-reactive T cells. The SFZ70 TCR was cloned from the SFZ70 hybridoma, which was generated from a CD4+ T cell isolated from the skin-draining peripheral lymph nodes (PLN) of a scurfy mouse. The SFZ70 hybridoma responds specifically to dendritic cells (DC) isolated from the PLN of wild-type mice but not to DC isolated from other tissues, and therefore appears to recognize a cutaneous antigen. SFZ70+RAG1-/- mice contain both peripheral CD4+Foxp3+ regulatory T cells (Tregs) and CD4+Foxp3- T cells and do not exhibit inflammation in the skin or other organs. To examine whether SFZ70 Tregs are required for maintenance of peripheral tolerance, we generated SFZ70 mice lacking functional Tregs by crossing SFZ70 mice to scurfy mice (SFZ70+RAG1-/-Foxp3sf/Y). SFZ70+RAG1-/-Foxp3sf/Y mice develop severe autoimmune disease characterized by lymphocytic infiltration of the skin and liver. Additionally, CD4+Foxp3- T cells from these mice show increased proliferation and display a CD62LloCD44hi activated phenotype. Our results show that in the absence of Tregs, an individual scurfy T cell-derived TCR is capable of inducing multi-organ autoimmune disease.
Identification and characterization of macrophage regulatory cells (Mac-regs) with immunoregulatory properties (89.38)
Authors: Zorro Manrique Soraya , Zorro Manrique Soraya , Duque Maria Adelaida , Dominguez Ana Lucia , Mirza Noweeda N , Hoelzinger Dominique , Smith Shannon E. , Lustgarten Joseph 
Published: January 2023

Abstract
Macrophages with suppressive characteristics such as Tumor associated macrophages or Myeloid derived suppressor cells have been defined showing regulatory function under inflammatory or polarizing conditions. Until now, there are no reports indicating that under normal, non-inflammatory or non-polarizing conditions, macrophages could have immunoregulatory functions. Utilizing knock-in Foxp3-GFP mice, we identified a new population of Foxp3 positive cells that were CD11b+F4/80+ cells. These cells were observed in spleen, lymph nodes, bone marrow and thymus. Similar to Tregs, the CD11b+F4/80+Foxp3+ macrophages inhibited T cell proliferation, whereas Foxp3neg macrophages did not. The Foxp3neg macrophages could be converted to express Foxp3. These induced-CD11b+F4/80+Foxp3+ cells displayed inhibitory properties similar to natural Foxp3pos macrophages. Based on the immunoregulatory properties of these cells, we termed them Macrophage regulatory cells (Mac-regs). These Mac-regs express CD68hiF4/80hiCTLA4hiGITRhiIL-4Rhi. Interestingly, GR-1 is not a differentiation marker. The cytokine, chemokine, growth factor and genomic profiles of Mac-regs are different compared to CD11b+F4/80+Foxp3-cells. For the first time, we demonstrated the occurrence of a natural population of macrophages displaying regulatory function which may contribute to the homeostatic balance of the immune system.
This research was supported by Grants from the NIH and AFAR.
VEGFR1 as a New surface marker for CD4+ Regulatory T cells (89.41)
Authors: Shin Jin Young , Lim Jong Hyung , Park Chung Gyu 
Published: January 2023

Abstract
Regulatory T cells are a specialized subpopulation of T cells that control immune response and thereby maintain immune system homeostasis and tolerance to self-antigens. The isolation and expansion of CD4+ Treg cells requires specific surface markers. Currently, CD25, CTLA-4 and GITR are used, but they are also expressed on the activated T cells. In this study, we identified vascular endothelial growth factor receptor 1 (VEGFR1) as a new surface marker for CD4+ regulatory T cells. We found that VEGFR1, a receptor for VEGF involved in angiogenesis, is constitutively expressed on the surface of T cells. CD4+ T cells that express high levels of VEGFR1 (0.5%-1% of CD4+ T cells) suppressed T cell activation as efficiently as CD4+CD25+ regulatory T cells (Treg cells). VEGFR1highCD4+ T cells are not overlapped with Foxp3+CD4+ or CD25+CD4+ T cells. We suggest that VEGFR1 can be a useful surface marker for CD4+ regulatory T cells and further characterization of VEGFR1highCD4+ T cells subset needs to be performed.
Developmental requirements of T follicular helper cells (90.10)
Authors: Nurieva Roza , Chung Yeonseok , Dong Chen 
Published: January 2023

Abstract
After activation, CD4+ helper T (Th) cells differentiate into distinct effector lineages. Th cell subset called T follicular helper (TFH) cells are recently found to be present in germinal centers and are characterized by their expression of chemokine (C-X-C motif) receptor 5 (CXCR5). Despite their potential importance in humoral immunity, the developmental regulation of TFH cells and their relationship with other Th subsets is unclear. We found that mouse TFH cells have a divergent gene expression profile from Th1, Th2 cells, and in vivo developed independently of these cell lineages. TFH cell generation was regulated by ICOS liagand expressed on B cells and was dependent on interleukin (IL)-21, IL-6 and signal transducer and activator of transcription 3 (STAT3). Although TFH cells shared IL-21 expression with Th17 cells, they did not express IL-17, IL-17F, IL-22. Moreover, differentiation of TFH cells did not require TGFβ or Th17-specific orphan nuclear receptors RORα?and RORγ in vivo. Most importantly, T cells activated in vitro in the presence of IL-21 but without TGFβ signaling preferentially acquired TFH gene expression and functioned to promote humoral immunity in vivo. Our data indicate that TFH cells are distinct in their gene expression, developmental regulation and immune function from Th1, Th2 or Th17 lineages.
The work is supported by a Scientist Development Grant from the American Heart Association.
Forced expression of suppressor of cytokine signaling 3 in T cells protects mice from concanavalin A-induced hepatitis (90.16)
Authors: Fushimi Soichiro , Takahata Tomohiro , Wakabayashi Hiroshi , Ogino Tetsuya , Kubo Masato , Matsukawa Akihiro 
Published: January 2023

Abstract
The regulatory mechanism behind T cell-mediated liver injury is not fully elucidated. Here, we demonstrate that forced expression of SOCS3 in T cells protects mice from a T cell dependent concanavalin A (ConA)-induced hepatitis. Mice with a T cell specific overexpression of SOCS3 (SOCS3-cTg) were resistant to ConA-hepatitis, as evidenced by decreased serum ALT level, reduced hepatic damage and improved mice survival relative to the control. Hepatic expression of T-bet, a Th1-specific transcription factor, was decreased in SOCS3-cTg liver relative to the control with the reduced expressions of Th1 associated cytokines (TNFa, IL-12, IFNg) and chemokines (CXCL9/10). Flow cytometric analysis of isolated hepatic lymphocytes demonstrated that activated CD4+T cells, cytotoxic T (Tc) cells and natural killer T (NKT) cells were significantly decreased in SOCS3-cTg liver. Expression of perforin and granzyme B, injurious molecules produced from Tc and NKT cells, was reduced in SOCS3-cTg liver. These results indicate that forced expression of SOCS3 in T cells prevents ConA-induced liver injury by inhibiting Th1 responses. SOCS3 delivery in T cells may be therapeutic strategy in T cell-mediated liver injury. Financial support: Grants-in-Aid from The Ministry of Education, Science, Sports and Culture, and The Ministry of Health and Welfare, Japan,
A critical role for microRNA miR-155 in CD8+ T cell responses (90.23)
Authors: STELEKATI ERIETTA , BOESTEANU ALINA C. , GRACIAS DONALD T. , MUELLER YVONNE M. , VIGORITO ELENA , NORTON JILLIAN A. , TURNER MARTIN , KATSIKIS PETER D. 
Published: January 2023

Abstract
The role of microRNAs in CD8+ T cells responses is largely unexplored. We have found that miR-155 is upregulated by 100-fold in activated CD8+ T cells. To test the in vivo role of miR-155 in CD8+ T cell responses, we examined bic/miR-155 deficient (bic-/-) CD8+ T cells in Influenza type A virus or Listeria monocytogenes (L.m.) infected mice. To demonstrate that miR-155 deficiency induces an intrinsic defect in CD8+ T cells, bic-/-OT-1+ and OT-1+ transgenic CD8+ T cells were adoptively transferred into C57BL/6 hosts, and then either infected with SIINFEKL peptide expressing influenza virus strain WSN-OVA or recombinant L.m. strain expressing OVA (L.m.-OVA). At day 10 post-infection the number of pulmonary bic-/-OT-1+ CD8+ T cells was reduced 3-fold compared to OT-1+ CD8+ T cells (p=0.01). With L.m.-OVA infection, day 7 post-infection numbers of splenic bic-/-OT-1+ CD8+ T cells were 10-fold lower than OT-1+ CD8+ T cells (p=0.0005). On day 3 post-infection however, no differences were found between OT-1+ or bic-/-OT-1+ CD8+ T cells transferred animals and both groups equally controlled the bacterial burden in the spleen compared to non-transferred control animals suggesting that bic-/-OT-1+ CD8+ T cells transfer normally and that miR-155 regulates CD8+ T cell responses at the later stages of infection. These findings demonstrate that miR-155 plays a critical role in CD8+ T cell responses against pathogens.
Nrf2 activation suppresses production of T cell cytokines and IgM in C57BL/6 mice (90.26)
Authors: Rockwell Cheryl E , Fields Patrick E , Crawford Robert B , Kaminski Norbert E , Klaassen Curtis D 
Published: January 2023

Abstract
Nrf2 is a transcription factor that upregulates cytoprotective genes in response to cellular stress. Nrf2 gene expression is induced in CD3+ cells by tert-butylhydroquinone (tBHQ), a known Nrf2 activator. In addition, tBHQ upregulates the Nrf2 target genes, Ho-1, Nqo1, and Gclc in wild-type, but not Nrf2-null CD3+ T cells. Furthermore, tBHQ and butylated hydroxyanisole (BHA), another Nrf2 activator, markedly inhibit IFNγ transcription in wild-type activated T cells, but have little effect on IFNγ transcription in Nrf2-null T cells. Likewise, tBHQ inhibits binding to both the AP-1 and NFκB response elements in wild-type CD3+ cells, but only modestly inhibits AP-1/NFκB binding in Nrf2-null CD3+ cells. Production of TNFα and IL-2 by activated T cells is also suppressed by tBHQ. In accordance with the aforementioned findings, tBHQ-treated mice exhibited diminished antibody production to sheep RBC, a T cell-dependent immune response. Collectively, the current studies suggest Nrf2 activation in CD3+ cells markedly inhibits T cell cytokine production and consequently, T cell-dependent responses, in vivo. The present studies suggest Nrf2 may represent a novel regulatory mechanism in mature murine T cells and thus may be a useful target for the development of new anti-inflammatory therapeutics. (Supported by NIH grants ES09716, ES07079, ES013714, ES09649, and RR021940.)
MHC haplotypes modulate strength of natural killer (NK) cell licensing (91.10)
Authors: Jonsson A. Helena , Yokoyama Wayne M. 
Published: January 2023

Abstract
NK cells react to cells that lack self-MHC class I. Yet, since many NK cells cannot recognize self-MHC, mechanisms such as NK cell licensing protect against autoreactivity. To become licensed, i.e. functionally competent to be triggered through its activation receptors, an NK cell must engage host MHC class I via at least one of its MHC class I-specific inhibitory receptors, such as the Ly49 family of receptors in the mouse. However, the general determinants of this process remain largely unknown. Herein, we investigated the licensing impact of the b, d, f, k, q, r, and s H2 haplotypes on Ly49A+ NK cells in MHC-congenic mice. Ex vivo PK136 (anti-NK1.1) stimulation assays indicated that licensing may not be a binary phenomenon as some Ly49A-MHC class I haplotype combinations produced an intermediate licensing phenotype. Ly49A surface accessibility, a measure of cis binding with MHC class I, and Ly49A tetramer binding displayed a similar variability among the MHC haplotypes. Taken together, the data indicate a correlation between strength of licensing and strength of binding of Ly49A receptors with MHC class I, both of which are inversely correlated with surface accessibility of Ly49A receptors. These findings suggest that NK cell licensing is modulated by the strength of the interaction of inhibitory receptors with host MHC class I.
Supported by HHMI and grants from the NIH.
Human lymphoid tissue inducer (LTi) cells are CD127+RORc+ and can be expanded ex vivo (91.11)
Authors: Crellin Natasha  K , Cupedo Tom , Trifari Sara , Kaplan Charles , Spits Hergen 
Published: January 2023

Abstract
Long recognized as essential for proper lymph node organogenesis during fetal development, recent evidence has suggested that LTi cells also play an important role in the adult. Recent work from our laboratory has identified the previously unknown human LTi as lineagenegCD127+RORc+ cells. In vitro studies suggest a direct relationship of LTi cells with CD127+RORc+ NK cells. Both LTi and CD127+ NK cells isolated from human tonsil produce IL-22, IL-17, TNFalpha, and lymphotoxin, but not IFNgamma. LTi cells are present in a low frequency in human tonsils, thus making detailed analysis challenging. Using a rigorous selection strategy, we have successfully purified LTi and CD127+ NK cells and expanded these cells 30-100 fold using a feeder cell mixture and IL-2. These expanded LTi and CD127+ NK cell lines maintain RORc expression and production of IL-22 and IL-17. Interestingly, following ex vivo expansion both LTi and CD127+ NK cells produce IFNgamma upon stimulation. An outstanding question remains the cytotoxic potential of LTi and CD127+ NK cells, which we can now investigate. Further, we are investigating the role of stimulatory cytokines in regulating IL-22 production from LTi and CD127+ NK cells. As aberrant regulation of IL-22 can contribute to inflammatory diseases, further understanding of this novel population of IL-22 producing cells is of great relevance.