bluuebunny/crossref_metadata_2025_split huggingface dataset:
α-MSH Induces CD4+CD25+FOXP3+ Cells and Suppress Activation of PBMCs from Pediatric Patients with Allergic Conjunctivitis
Authors: Nieto Jane Eyre , Jiménez Martínez María C. , Fest Scarlett , Casanova Israel , Ayala Julio , Salazar Luis Alberto , Velázquez Henry 
Published: January 2023

Abstract

Introduction
Allergic conjunctivitis (AC) is one of the most frequent ophthalmological diseases. AC is characterized by ocular surface inflammation and systemic immune dysregulation with low frequency of CD4+CD25+FOXP3+ regulatory T cells and higher frequency of circulating effector T cells. It has been reported that α-melanocyte stimulating hormone (α-MSH) constitutes one of the principal mechanisms of immune regulation in the anterior chamber of the eye and the ocular surface, promoting the differentiation of Tregs in a murine model of experimental autoimmune uveitis and suppressing autoreactive T cells in a murine model of experimental autoimmune encephalomyelitis. This work aimed to evaluate the involvement of α-MSH in Tregs induction in cells obtained from patients with AC.

Methods
Peripheral blood mononuclear cells (PBMC) were obtained from blood sampling after assent consent was obtained from pediatric patients sensitized to house dust mite (HDM) and diagnostic with AC. PBMC were cultured with HDM and/or α-MSH. After 72h of culture, PBMC were harvested and stained with anti-CD4-AmCyan, anti-CD25-PE, anti-FOXP3-FITC and anti-CD69-APC-Cy7 and analyzed by flow cytometry. IL-2, IL-4, IL-6, IL-10, IL-17, TNF-a and IFN-γ were determined by cytometric bead arrays.

Results
A significant increase in the frequency of CD4+CD25+FOXP3+ T cells and a significant decrease in the frequency of CD4+CD69+ cells were observed in HDM+α-MSH stimulated cells, when compared with HDM. Remarkably, IL-4 showed a significant decrease in cultured cells stimulated with HDM+α-MSH.

Conclusion
These results suggest that a-MSH inhibit the IL-4 production, reestablishing the development of Treg cells and control pathogenic CD4+CD69+ T cells.
Regulation of CD8+T-lymphocytes by eEF-2K
Authors: Das Jugal Kishore , Song Jianxun 
Published: January 2023

Abstract
Eukaryotic elongation factor-2 kinase (eEF-2K) is a conserved protein kinase which associates multiple upstream signals with protein synthesis and cellular metabolism. Reprogramming of the cellular metabolic microenvironment in T-lymphocytes is a hallmark of several immune-pathophysiological conditions. However, the role of eEF-2K in T-cell metabolism and signaling remain unclear. The aim of the present study was to unravel the critical role of eEF-2K in regulation of cytotoxic CD8+T-lymphocytes (CTLs).
Primary CTLs from wild type (WT) and eEF-2K knock-out (KO) C57BL/6 mice were stimulated with anti-CD3 and CD28 antibodies and examined for their survival, proliferation and cytokine production. The cellular metabolism was analyzed using Seahorse Extracellular Flux analyzer. A combination of western blotting and flowcytometric analysis was used to assess the key mediators of the central metabolic Akt-PI3k-mTOR pathway.
Following activation, eEF-2K KO CTLs had significantly reduced survival on Day 4 (4-fold change; p&lt;0.05) but proliferated more rapidly as compared to WT CTLs. The oxidative metabolism of CTLs from eEF-2K KO mice was higher leading to their early senescence. Our western-blotting analysis showed the dysfunctional metabolism of eEF-2K KO CTLs was orchestrated by enhanced activation of Akt-PI3k-mTOR signaling pathway. Correlatively, eEF-2K KO CTLs had dysfunctional IL-2, PD-1, CD 62L, CD27 and CD226 expression which was restored by treatment with rapamycin.
Collectively, our results identify that eEF-2K not only plays a crucial role in CTL activation and signaling, but also regulates senescence. These findings may be useful in designing novel strategies by targeting eEF-2K-based immunotherapy.
You are what you eat: CD46 regulated amino acid usage dictates T cell function
Authors: West Erin E , Freeley Simon , Kaminski Marcin M , Veenbergen Sharon , Lee Duck-Yeon , St. John-Williams Lisa , Thompson J. Will , Green Douglas R. , Scholl-Buergi Sabine , Karall Daniela , Huemer Martina , Kemper Claudia 
Published: January 2023

Abstract
Engagement of the complement receptor CD46 on T cells drives Th1 responses and upregulates nutrient and amino acid channels, such as GLUT1 and LAT1. We found that CD46 stimulation upregulates both the arginine transporter SLC7A1 (CAT-1) on human CD4 T cells and, unexpectedly, Arginase 1 expression in these cells, indicating that CD46 may regulate arginine metabolism in T cells. While Arginase 1 has been well characterized in macrophages where it is associated with the IL-10 secreting M2 type, its function in T cells has not been described. During contraction human Th1 cells switch from IFN-γ to IL-10 production and to a self-regulatory phenotype, thus we assessed the role of Arginase 1 in Th1 induction and/or contraction. Surprisingly, CD4 T cells isolated from four patients with rare Arginase 1 deficiency initially mount Th1 responses but display significantly increased IL-10 switching with earlier cellular collapse when compared to healthy control cells. Importantly, although T cells from patients with Arginase 1 deficiency have increased arginine levels, as expected, they produce normal levels of polyamines and NO. Metabolic profiling of the patients’ cells demonstrates that they shunt into a compensatory ‘glutamine usage pathway’ for their critical ornithine and polyamine generation. Analysis of changes in glutamine metabolites and their corresponding downstream pathways, along with in vivo influenza infections of Arg1fl/fl CD4-cre+ mice validate and further define the in vivo role of this novel T cell modulating pathway. Overall, these data demonstrate an unexpected intrinsic role for Arginase 1 and unveil an important compensatory mechanism used to maintain protective Th1 function in the absence of normal arginine catabolism.
The costimulatory molecule ICOS promotes establishment of resident memory CD8+ T cells
Authors: Peng Changwei , da Silva Henrique Borges , Wang Haiguang , Jameson Stephen 
Published: January 2023

Abstract
Resident memory T cells (TRM) are critical for localized protective immunity in non-lymphoid tissues, but the signals involved in generating TRM are incompletely defined. Inducible T-cell costimulator (ICOS) is a costimulatory molecule expressed on activated T cells, and is highly expressed on TRM compared to recirculating memory CD8+ T cell subsets. While the role of ICOS has been well elaborated in T follicular helper cells, its function in CD8+ T cells is largely unexplored. Using both mixed bone-marrow chimeras and adoptive co-transfer of antigen-specific CD8+ T cells with acute infection models, we found ICOS deficient CD8+ T cells showed minimal defects in the initial effector expansion and the generation of recirculating memory population. However, consistent with its expression pattern, ICOS deficiency significantly compromised the establishment of CD8+ TRM cells in diverse non-lymphoid tissues. We further confirmed that the interaction between ICOS ligand (ICOSL) and ICOS is essential for CD8+ T cells tissue residency, and the defect of Icos−/− CD8+ T cells tissue residency can be detected even at early time points post infection, indicating that ICOS signaling affects initial retention of activated CD8+ T cells in non-lymphoid tissues. To gain a better understanding of the ICOS signaling, we used shRNA to knockdown KLF2, a transcription factor that we showed previously inhibits generation of CD8+ TRM and which is negatively regulated by ICOS stimulation in CD4+ Tfh. Our data support the model that ICOS-mediated down-regulation of KLF2 is important for the establishment of CD8+ TRM. Further investigations into the mechanistic basis by which ICOS signaling promotes CD8+ T cells tissue residency are ongoing.
Antigen presentation by CD301b+ dermal dendritic cells dictates CD4+ T cell fate
Authors: Tatsumi Naoya , Iwasaki Akiko , Kumamoto Yosuke 
Published: January 2023

Abstract
Different subsets of dendritic cells (DCs) induce different types of effector CD4T cells. Naïve mouse skin is populated with three major DC subsets, including epidermal Langerhans cells, CD103+ dermal DCs and CD301b+ dermal DCs, all of which migrate to the draining lymph nodes (dLNs). We showed previously that CD301b+DCs are required for the differentiation of antigen specific T helper type 2 (Th2) cells upon immunization with ovalbumin (OVA) and papain in the footpad. However, the mechanism by which CD301b+DCs induce Th2 differentiation is unclear. Here, we examined the role of antigen presentation by CD301b+DCs in the priming and Th2 differentiation of antigen-specific CD4T cells. As in CD301b+DC-depleted mice, mice lacking MHC class II (MHCII) specifically in CD301b+ cells (CD301bΔMHCII mice) showed significantly reduced IL-4 production from OVA-specific OT-II CD4T cells 7 days after immunization, suggesting that cognate interaction between CD301b+DCs and CD4T cells is required for the development of Th2 cells. In addition, although the overall cell cycle progression of OT-II cells was unaffected, their entry into the cell cycle was significantly delayed. In both CD301b+DC-depleted and CD301bΔMHCII mice, this reduction of OT-II cells was associated with impaired retention of OT-II cells in the dLN at much earlier timing. Furthermore, CD301b+DCs were required for retaining and activating wild-type polyclonal CD4T cells in the dLNs in an MHCII-dependent manner. These results indicate that CD301b+DCs are required for effective priming of CD4T cells and Th2 differentiation through their cognate interaction with antigen-specific CD4T cells.
Human Tc17 cells harbor potent immune suppressive potential, whereas Tc1 cells lack suppressive ability
Authors: Renavikar Pranav S , Crawford Michael P , Sinha Sushmita , Karandikar Nitin J 
Published: January 2023

Abstract
Regulatory T-cells keep untoward immune responses under control. In several autoimmune diseases, there is a substantial regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that acute relapses of Multiple Sclerosis are characterized by a deficit of CD8+ T-cell mediated immune-suppression. Similar to CD4+ T-cells, lineages for CD8+ cytotoxic T-cells (Tc) are predominantly determined by the cytokine milieu during differentiation. We hypothesized that distinct Tc lineages may harbor differential ability to suppress effector CD4+ T-cell responses. To test this hypothesis, we obtained purified human naïve CD8+ T-cells and activated them in different in-vitro conditions to differentiate them toward Tc0 (control), Tc1, Tc2 and Tc17 lineages. We then tested their ability to suppress various types of CD4+ T-cells in flow cytometric suppression assays. We observed that Tc0 controls and Tc2 cells had comparable suppression. However, Tc1 cells showed significant loss of suppressive ability. Interestingly, Tc17 cells exhibited significantly greater suppression of effector cells of various lineages (including bulk ex-vivo CD4+ T-cells as well as in-vitro differentiated Th1 and Th17 cells). Tc17 cells also showed the greatest proportion of CD8+ T-cells with a terminally differentiated phenotype (CD27−/CD45RO−), which we have previously shown to harbor the highest suppressive ability in a neuroantigen-specific setting. These studies illustrate that Tc17 cells, known to play a vital role in infection, tumor and autoimmunity, may have an important immune-regulatory function against effector CD4+ T-cells that could be harnessed in the design of CD8+ T-cell based immune-modulatory therapy.
Short-chain fatty acids regulate regulatory T cells and intestinal pathology during oral mucosal infection
Authors: Bhaskaran Natarajan , Schneider Elizabeth , Pandiyan Pushpa 
Published: January 2023

Abstract
Complex interactions between the microbial flora and the host exert sophisticated means of immune tolerance and regulation mechanisms. One mechanism is by inducing the accumulation of regulatory T (Treg) cells. Here we show that the depletion of resident bacteria using antibiotics (Abx) causes oral and gut immunopathology during Oropharyngeal Candidiasis (OPC) infection. Abx treatment causes decrease in the frequency of Foxp3+ regulatory cells (Tregs) and IL-17A producing T cells, with a concomitant increase in oral tissue pathology. Although oral C. albicans (CA) is commonly controlled in the oral cavity, Abx treatment led to CA dependent oral and gut inflammation. The combination of short chain fatty acids (SCFA) partially controlled the pathology in Abx treated mice, correlating to an increase in the frequency of Foxp3+, IL-17A+, and Foxp3+IL-17A+ double positive (Treg17) cells in tongue and oral draining lymph nodes. SCFA enabled the restoration of Th17 cells and Treg cells and oral infection clearance, but did not reverse weight loss. Because SCFA treatment did not fully reverse the gut inflammation, it is evident that resident microbiota have SCFA independent homeostatic mechanisms in gut mucosa. We also found that SCFA potently induce Foxp3 and IL-17A expression in CD4+ T cells, depending on the cytokine milieu in vitro. Taken together, our data reveal that SCFA derived from resident bacteria play a critical role in controlling gut immunopathology by regulating T cell cytokines during oral mucosal infections.
Recently alloactivated CD4+CD8−CD25+T regulatory cells express CD8alpha and are potent suppressor cells
Authors: Hall Bruce Milne , Verma Nirupama Darshan , Robinson Catherine Margaret , Wang Chaunmin , Sharland Alexandra , Tran Giang , Wilcox Paul , Hodgkinson Suzanne Jean 
Published: January 2023

Abstract
Therapy with antigen-specific CD4+CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are non-antigen specific and weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells and IL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rb2) and are more potent alloantigen-specific regulators that we call Ts1 cells.
This study examined other markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+CD25+Foxp3+Treg. After culture of naïve DA CD4+CD8−CD25+T cells with rIL-2 and PVG alloantigen, CD8a was expressed on 10–20% and CD8b on &lt;5% of these cells. RT-PCR showed the CD8+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4, a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+CD8+CD25+Treg consistent with the CD8a+ cells expressing IL-12R. In MLC, the CD8+ fraction had greater suppression than the mixed Ts1 population, whereas the CD4+CD8−CD25+T cells had less suppression. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8a cells did not prevent rejection.
This study showed the expression of CD8alpha by rIL-2 and alloantigen activation of CD4+CD8−CD25+Foxp3+T cells was a marker of alloantigen-specific Treg and may be of use to enrich alloantigen-specific Treg.
A protective role of IFN-γ in T cell-mediated colitis by regulation of Treg/Th17 via induction of indoleamine-2,3-deoxygenase
Authors: Zheng Song Guo , Xu Zhenjian , Wang Julie 
Published: January 2023

Abstract
IFN-γ is an important Th1 type cytokine and has a paradoxical effect on the pathogenesis of several chronic inflammatory disorders, including inflammatory bowel disease. Here we demonstrate that IFN-γ plays a protective effect on the model of T cell-mediated colitis. Compare with wild-type control, adoptive transfer of CD4+CD62L+ naïve T cells isolated from IFN-γ−/−mice into Rag1−/−mice induced a more severe wasting disease, correlating with increased expression of Th17 cells but decreased expression of Foxp3+ T regulatory cells in colon tissue and peripheral lymphoid organs. Additionally, infusion of CD4+CD62L+ naïve T cells isolated from IFN-γ receptor knock-out mice into recipient Rag1−/−mice also elicited a more severe wasting disease when compared to infusion of naïve T cells isolated from wild-type mice. IFN-γ induced indoleamine-2,3-dioxgenase (IDO), an enzyme in the metabolism of tryptophan, plays a critical roles in immune responses regulating the balance between Treg and Th17 cells. Our data suggest that IFN-γ provides a protective function in T cell-mediated intestinal inflammation by regulation of Treg and Th17 via the induction of IDO.
Regulatory T cells limit unconventional memory to preserve the capacity to mount protective CD8 memory responses to pathogens
Authors: Graham Jessica B , Da Costa Andreia S. , Swarts Jessica L , Lund Jennifer M 
Published: January 2023

Abstract
Immunological memory exists so that following infection, an expanded population of pathogen-specific lymphocytes can rapidly and efficiently control infection in the case of re-exposure. However, in the case of CD8+ T lymphocytes, a population of unconventional CD44+CD122+ virtual memory T cells (TVM) has been described that possesses many, though not all, features of “true memory” T cells, without the requirement of first encountering cognate antigen. Here, we demonstrate a novel role for regulatory T cell-mediated restraint of TVM through limiting IL-15 trans-presentation by CD11b+ dendritic cells. Further, we show that keeping TVM in check ensures development of functional, antigen-specific “true” memory phenotype CD8 T cells that can assist in pathogen control upon re-exposure.
IL-34 differentiation of immunosuppressive macrophage
Authors: Kelly-Scumpia Kindra , Shirazi Roksana , Modlin Robert 
Published: January 2023

Abstract
Myeloid cells are necessary for effective immune responses in infection. Myeloid cells enter the skin differentiate into effector myeloid cells, such as macrophages (MΦ). The local and systemic factors responsible for this phenomena are poorly understood. Leprosy provides a human model to study myeloid cells in the skin as exposure of patients to the same pathogen, Mycobacterium leprae, results in distinct disease manifestations. In self-limited, tuberculoid leprosy (T-lep), appropriate monocyte activation results in differentiation into effector M1 MΦ that produce antimicrobial peptides and control M. leprae. In lepromatous leprosy (L-lep), inadequate immune responses fail to clear M. leprae. IL-15 and IL-10 were previously found to promote effector M1 MΦ in T-lep and immunosuppressive M2 MΦ in L-lep patients, respectively, but whether other immunologic factors affect MΦ differentiation in leprosy has not been investigated. Herein, we find IL-34, a cytokine known to drive M2 MΦ development in vitro, is increased in L-lep lesions. Differentiation of monocyte derived MΦ (MDM) with IL-34 results in increased IL-10 production following stimulation with M. leprae when compared to M-CSF derived MDM. Similar to IL-10 derived MDM, IL-34 derived MDM demonstrate increased phagocytic activity, but surprisingly, are able to activate a vitamin D dependent antimicrobial response similar to IL-15 derived MDM. These data indicate that IL-34 drives an alternative pathway of M2 MΦ development. IL-34 MDM produce anti-inflammatory cytokines, but retain the ability to induce antimicrobial responses. These findings raise the potential of IL-34 or IL-34 MDM to treat inflammatory skin disorders while retaining the ability to fight infection.
Sympathetic nervous tone influences anti-tumor immunity by mediating accumulation of myeloid-derived suppressor cells and regulatory T-cells
Authors: Nevin James Timothy , Corwin William L. , Srivastava Pramod K. 
Published: January 2023

Abstract
Sympathetic nerves innervate primary and secondary lymphoid organs, providing a means by which nervous system signaling can affect cellular immunity. For example, signaling by sympathetic nerves that innervate the spleen and bone marrow can regulate the development of myeloid cells. In cancer, aberrant myeloid development has been shown to drive accumulation of myeloid-derived suppressor cells (MDSCs) that suppress the anti-tumor immune response and are associated with poor prognosis. Given the known regulatory effect of sympathetic nervous system (SNS) signaling on myelopoiesis and the consequences of aberrant myeloid development in cancer, we hypothesized that the SNS plays an important role in regulating the immune response to cancer by influencing accumulation of MDSCs. Here, we demonstrate that inhibition of tonic SNS signaling compromises the anti-tumor immune response and results in increased tumor growth. We show that chemical ablation of the SNS by peripheral administration of 6-hydroxydopamine disrupts normal myeloid development in the bone marrow and results in expansion of CD11b+Ly6G+ polymorphonuclear MDSC and CD11b+ Ly6Chi monocytic MDSC in tumor-bearing mice. We show that these MDSC are able to potently suppress T-cell proliferation and mediate the expansion of regulatory T-cells that further inhibit the anti-tumor immune response. These data demonstrate how SNS-mediated regulation of immune development and function plays an important role in instructing the anti-tumor immune response. These findings have the potential to improve our understanding of the interplay between the nervous and immune systems, and better inform treatment of cancer and other immune-mediated pathologies.
PI3K activated tumors evade tumor immunity by promoting an inhibitory myeloid microenvironment
Authors: Collins Natalie B , Abosy Rose Al , Miller Brian , Bi Kevin , Manguso Robert , Yates Kathleen , Haining W. Nicholas 
Published: January 2023

Abstract
Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood. Here we use an in vivo screen of known cancer-associated somatic mutations in immunocompetent mouse tumor models treated with checkpoint blockade to identify oncogenes that confer immune evasion. We found that a catalytically active mutation in Phospho-Inositol 3 Kinase (PI3K), PIK3CA c.3140A&gt;G (H1047R) confers selective growth advantage after immunotherapy. Pharmacologic PI3K inhibition resensitizes mutant tumors to immunotherapy with anti-PD-1. The tumor microenvironment (TME) in PIK3CA H1047R-expressing tumors has fewer infiltrating CD8+ T cells after immunotherapy but is enriched for immune inhibitory myeloid cells. Inhibition of myeloid infiltration in PIK3CA H1047R tumors results in increased sensitivity to PD-1 checkpoint blockade. Thus PI3K has a role in tumor immune evasion mediated by establishment of an inhibitory myeloid microenvironment in addition to its well-described, cell-intrinsic oncogenic role. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. More generally, our data suggest a rationale to combine PI3K inhibition with immunotherapy of PI3KCA mutant tumors.