bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ectopic expression of CD127 restores the numbers of thymic and peripheral T cell populations in adenosine A2A receptor deficient mouse
Authors: Cekic Caglar , Linden Joel M , Savas Ali Can , Kayhan Merve , Koyas Altay , Akdemir Imran 
Published: January 2023

Abstract
Inhibition of proximal TCR signals by adenosine A2A receptors (A2AR) is important for T cell development and maintaining T cell quiescence in vivo. Deletion of A2ARs causes accelerated growth of B16 and MB49 tumors, which is associated with reduced T cell accumulation in tumors and decreased CD127 expression and interleukin-7 responsiveness. Here we showed that ectopic expression of CD127 in A2AR deficient mice restores normal numbers of thymic populations and IL-7 responsiveness of T cells. Ectopic expression of CD127 in A2AR deficient mice also caused accumulation of similar numbers of T cells in the periphery as compared to A2AR proficient mice. Growth of B16 tumors in A2AR deficient mice was accelerated as compared to A2AR proficient mice. However, growth of B16 tumors was comparable between A2AR deficient or proficient mice ectopically expressing CD127. Adenosine A2A receptor deletion or ectopic CD127 expression did not change Vbeta selection suggesting changes in T cell repertoire may not be involved in increased tumor growth and reduced T cell numbers in A2AR deficient mice. Interestingly, tumor growth in A2AR and CD127 double deficient mice was slower as compared to CD127 deficient mice. Finally, adenosine preconditioning of engineered T cells significantly reduced lung colonization of B16OVA tumors and persistence of engineered T cells. Overall these results suggest that CD127 regulation by adenosine is important for T cell maintenance and functional responses in vivo and blockade of A2AR to improve anti-tumor immune responses should be further promoted by providing signals for T cell survival.
Adrenergic signaling impairs activation of CD8+ T cells by blocking metabolic reprogramming
Authors: Qiao Guanxi , Bucsek Mark J , Hylander Bonnie L , Repasky Elizabeth A 
Published: January 2023

Abstract
Adrenergic stress promotes tumor progression by several mechanisms. Mice housed at standard housing temperature (ST, 22°C) experience chronic adrenergic cold stress sufficient to elevate norepinephrine levels compared to mice housed at thermoneutrality (TT, 30°C) and we found that tumors grow faster at ST. We have also previously reported that the anti-tumor immune response is suppressed at ST. Tumor infiltrating CD8+ T cells from these mice have reduced expression of activation and effector function markers. These deficits are reversed by housing mice at TT which reduced adrenergic stress or by treating mice at ST with the β-adrenergic receptor antagonist propranolol. Coincident with this effect, we see increased cell surface expression of the glucose transporter-1 on CD8+ T cells, which is critical for glycolysis. Based on the fact that T cell activation and function require up-regulation of glycolysis (i.e. “metabolic reprogramming”), we hypothesize that adrenergic signaling impairs the antitumor efficacy of CD8+ T cells by impairing metabolic reprogramming. To test this hypothesis, CD8+ T cells were isolated and activated and treated +/− the β-AR agonist isoproterenol (ISO). Using Seahorse Extracellular Flux Analysis to compare the bioenergetics of control and ISO treated CD8+ T cells, we found that adrenergic signaling significantly reduced ECAR (glycolysis) and increased the ratio of oxidative phosphorylation/glycolytic rate (OCR/ECAR). These data support the idea that adrenergic signaling blocks metabolic reprogramming in CD8+ T cells thereby inhibiting T cell activation. Current work is focused on identifying the precise intracellular pathways by which adrenergic signaling and T cell metabolism intersect.
CD73 expression in cancer-associated fibroblasts exacerbates immune suppression and promotes tumor progression via augmenting adenosine accumulation in the tumor microenvironment
Authors: Yu Miao , Guo Gang , Huang Lei , Mellor Andrew , CUI YAN 
Published: January 2023

Abstract
CD73, an ecto-5′-nucleotidase, is the major extracellular adenosine-generating enzyme that converts AMP to immunosuppressive adenosine (ADO). Previous studies demonstrated that CD73-mediated ADO production in the tumor microenvironment (TME) is an immune evasion mechanism explored by tumors, myeloid-derived suppressor cell (MDSCs), and regulatory T cells. Targeted suppression of CD73, either via CD73 blocking antibody or inhibitors, suppresses tumor progression and metastasis. Given the complexity of the TME and crucial involvement of cancer-associated fibroblasts (CAFs) in immunosuppression and tumor progression, we explored the contribution of CD73 in CAFs to tumor progression. Using a CD73-negatvie EL4 tumor in C57BL/6 WT and CD73KO mice, we observed a high level of CD73 expression in CAFs, associated with their higher capacity of converting extracellular AMP to ADO than that of lymphocytes and myeloid cells in culture. Interestingly, as tumor progresses, CAFs in the TME of WT mice expended extensively to form an interconnected network and the percentage of CD73+ CAFs increases, while that of tumor infiltrating lymphocytes, especially CD8 T cells, decreases. However, in CD73KO mice, EL4 tumor progression was greatly delayed, associated with their significantly higher level of tumor-infiltrating CD8+ cytotoxic T cells. Functional analysis of fibroblastic stromal cells confirmed that CD73 inactivation greatly diminished their ability to generate extracellular ADO and subsequent suppression of T cell activation. Our results suggest that CD73 also represents one of the important mechanisms of CAF-mediated immunosuppression. We will discuss the potential environmental factors that enforce CD73 expression in CAFs.
Roles of SOCS1 for establishment of mycobacterial infection
Authors: Soma Shogo , Yasutomi Yasuhiro 
Published: January 2023

Abstract

Background
Suppressor of cytokine signaling (SOCS) 1 plays a crucial role in the negative regulation of JAK/STAT pathway. The SOCS1 is strongly upregulated by infection with several pathogens include M. bovis bacillus Calmette-Guérin (BCG). Since the function of SOCS1 induced by infection is not fully understood. In present study, we establish recombinant BCG which express a dominant-negative SOCS1 (rBCG-SOCS1DN) which acts as antagonist for SOCS1 signals.

Methods
C57BL/6, Rag1−/−, Nos2−/− and Rag1−/−Nos2−/− (DKO) mice were inoculated intratracheally with rBCGSOCS1DN or vector control rBCG (rBCG-pSO). Lungs and bronchoalveolar lavage fluids were harvested and analyzed. The mRNA and supernatants from bone marrow-derived myeloid dendritic cells (BMmDCs) infected with rBCG were harvested and nos2 gene expression and the production of nitric oxcide (NO) were measured. These cells were analized by electron microscopy.

Results
The amount of rBCG-SOCS1DN was significantly reduced by not only C57BL/6 but also Rag1−/− mice comparison with those of rBCG-pSO. The cytokine/chemokine profiles were not significant difference between rBCG-SOCS1DN and rBCG-pSO; however, nos2 gene expression and NO release from BMmDCs infected with rBCG-SOCS1DN were significantly higher than BMmDCs infected with rBCG-pSO. In Nos2−/− and DKO mice, there were no significant difference of bacterial burdens between rBCG-SOCS1DN and rBCG-pSO. Furthermore, the BMmDCs infected rBCG-SOCS1DN were necrotic damaged less than BMmDCs infected with rBCG-pSO.

Conclusions
These data suggest that BCG induce SOCS1 activation for evasion of microbicidal mechanism by nitric oxide from the innate immune responses.
The non-classical CD8+ T cell response to murine cytomegalovirus
Authors: Anderson Courtney K , Reilly Emma C , Lee Angus Y , Vance Russell E , Brossay Laurent 
Published: January 2023

Abstract
There is a growing interest in the role of MHC class Ib-restricted CD8+ T cells, referred to as non-classical T cells, such as MAIT cells and NKT cells. Non-classical CD8+ T cells have been shown to participate during the immune response towards a number of bacterial and viral pathogens. However, the overall role of these cells remains largely undetermined. We sought to investigate their contribution during murine cytomegalovirus (MCMV) infection, a well-established model for human cytomegalovirus. To circumvent the known role of conventional CD8+ T cells we utilize KbDb−/− mice, which lack MHC class Ia molecules. Following MCMV challenge, a subset of non-classical CD8+ T cells undergoes robust expansion, gains effector functions, and subsequently contracts. Interestingly, there is a prolonged inflammatory phenotype not observed in B6 or β2m−/− control animals. Non-classical CD8+ T cells from long-term infected KbDb−/− mice are also capable of robust proliferation in response to secondary MCMV infection, indicating that these T cells exhibit a memory phenotype. Using RAGKbDb−/− animals, we determined that adoptively transferred non-classical CD8+ T cells are sufficient to protect against MCMV-induced lethality. The population we describe is more phenotypically similar to conventional CD8+ T cells than innate non-classical T cells. Altogether, our data indicate that MHC class Ib-restricted CD8+ T cells may substitute for conventional CD8+ T cells when their functions are compromised during CMV immunoevasion.
Cytokine induced SH2-containing (CIS) protein mediated intrinsic and extrinsic CD8+ T cell regulation
Authors: Dlugolenski Daniel Aaron , Ward Alister , Stambas John 
Published: January 2023

Abstract
Small nuclear polymorphisms in CIS exhibit strong correlation with enhanced disease susceptibility in humans. CIS is a member of the SOCS family of proteins, and SOCS proteins are intracellular negative regulators of JAK/STAT signalling. The SH2 domain of CIS inhibits STAT5 interaction with JAK1 and JAK3. STAT5 is critical in downstream signalling of IL-2 and IL-15 in CD4+ and CD8+ T cells. IL-2 and IL-15 signalling are important in the regulation of critical T cell checkpoints including activation, proliferation, survival and differentiation. The regulatory role of CIS in immune cell development and function is relatively undefined, and recent studies have provided brief insights on the role of CIS in CD8+ T cell biology and its overall contribution to infection and immunity. Using CIS knock-out mice, we show that CIS plays a significant role in intrinsic and extrinsic regulation of CD8+ T cell responses to influenza A virus infection. Infection in the absence of CIS results in reduced morbidity and improved recovery compared with wildtype mice associated with enhanced recruitment of influenza A virus specific CD8+ T cells in the lungs of knockout mice. The observed changes in influenza A virus specific CD8+ T cells is supported by intrinsic modification of the proliferative capacity of CD8+ T cells lacking CIS. We also observe significant changes in DC subsets in the lung and mediastinal lymph nodes altering the extrinsic regulation of influenza specific CD8+ T cells. This work highlights a comprehensive understanding of the role of CIS in viral immunity and CD8+ T cell biology.
Efficient activation of latent HIV reservoir in human memory T cells by depletion of regulatory T cells in humanized mice in vivo
Authors: Li Guangming , Nunoya Jun-ichi , Reszka-Blanco Natalia , Cheng Liang , Tsao Li-Chung , Su Lishan 
Published: January 2023

Abstract
Regulatory T (Treg) cells play an important role in modulating immune activation and human immunodeficiency virus type 1 (HIV-1) infection. However, the role of Treg cells in HIV-1 latency establishment or maintenance in vivo remains unknown because of the lack of a robust model. We have established a humanized mouse model that supports long-term stable HIV-1 replication. When treated with combination antiretroviral therapy (cART), HIV-1 infection was stably suppressed to undetectable levels. Upon cART interruption, HIV-1 replication rebounded rapidly to pre-treatment levels. Interestingly, HIV-1 viral replication was significantly increased upon Treg cell depletion under effective cART. The HIV-1 reactivation during cART was mainly through increased gene expression from T cells. The rebound viruses during cART did not acquire drug resistance mutations. We found that most activated HIV-1 reservoir target cells were CD4 memory T cells in all lymphoid organs. These findings demonstrate that Treg cells suppress HIV-1 replication and its reactivation from latently infected T cells in vivo. Treg cell depletion provides an efficient way to reverse latency and reactivate HIV-1 reservoirs in vivo.
The CD38+ HLA-DR+ PD-1+ CD4 T cell population represents a short-lived part of the viral reservoir and predicts poor immunologic recovery upon initiation of ART
Authors: Eller Michael A. , Creegan Matthew , Hong Ting , Nau Marty , Slike Bonnie M. , Krebs Shelly J. , McElrath M. Juliana , Katabira Elly T , Michael Nelson L. , Robb Merlin L. , Tovanabutra Sodsai , Baeten Jared M. , Sandberg Johan K. 
Published: January 2023

Abstract
The activated PD-1+ CD4 T cell population is associated with disease progression in untreated HIV-1 infection, and with residual viral replication in individuals on ART. Few studies have examined cell associated viral load (CAVL) in phenotypically different activated CD4 T cell populations to define the HIV reservoir. We followed 32 HIV-1 chronically infected individuals, from Kampala, Uganda, and determined their CD4 T cell counts, and viral load at baseline, 6, and 12 months after the initiation of ART. Peripheral blood T cell populations were sorted based on activation profiles and gag DNA was measured to determine CAVL within these populations. Soluble inflammatory factors were measured in plasma using a multiplexed platform. The median HIV-1 viral load declined from 95,315 copies/ml at baseline to below detection for all patients after 12 months of ART, whereas CD4 T cells counts averaged 204 cells/μl at baseline and increased to 373 cells/μl by month 12. Median levels of the activated PD-1+ CD4 T cell population contracted from 4.5% of CD4 T cells at baseline to 2.3% of CD4 T cells after 12 months of ART. Baseline levels of activated PD-1+ CD4 T cells positively correlated with plasma levels of IP-10 (R2=0.362, P&lt;0.001) and TNFRII (R2=0.237, P=0.006). Higher baseline level of activated PD-1 positive CD4 T cells was associated with poorer CD4 T cell recovery after 12 months of ART (R2=0.240, P=0.039). CAVL was similar within the activated PD-1+ CD4 T cell population as other CD4 populations at baseline, but significantly lower after 12 months of ART compared to baseline. Taken together, the activated PD-1+ CD4 T cell population is a short-lived component of the viral reservoir and high levels of these cells predict poor immunologic recovery on ART.
HTLV-1 infection and neuropathogenesis in the context of Rag1−/−γc−/− (RAG1-hu) and BLT mice
Authors: Madagula Kiran Kumar , Ginwala Rashida , Caruso Breanna , Khan Zafar K , Chew Glen M , Pattekar Ajinkya , Corley Michael J. , Loonawat Ronak , Jacobson Steven , Sreedhar Sreesha , Ndhlovu Lishomwa C , Jain Pooja 
Published: January 2023

Abstract
To date, the lack of a suitable small animal model has hindered our quest to understand the immuno- and neuropathogenesis of HTLV-1, the causative agent of chronic disabling neuroinflammatory disease HAM/TSP. Host immune response that plays a critical role in the outcome of HTLV-1 infection could be better tested in the context of humanized (hu) mice. Thus, we infected neonatal and adult Balb/c-Rag1−/−γc−/− (Rag1) as well as Bone marrow-Liver-Thymic (BLT) mice with HTLV-1. Proviral load (PVL) was determined in the peripheral blood, spleen, and other organs by droplet digital PCR. Within blood, PVL and viral protein Tax was detected as early as 2 wks post-infection (wpi). Tax showed peak expression at 14 wpi in Rag1 mice with continued expression until 16 weeks. Both PVL and Tax expression was considerably higher in the adult Rag1 mice as compared to the neonates with the latter showing less than 20% PVL in the peripheral blood, brain, and liver. Moreover, signs of lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption were observed in the spinal cord and brain of infected mice. Thus far, several members of the CD28:B7 family of co-signaling molecules have been associated with T-cell dysfunctions in HTLV-infected patients. We found increased expression of PD-1, TIGIT and TIM-3 on CD8+ T cells in the CNS of infected hu-mice. This represents the first attempt to establish HTLV-1 neuropathogenesis in the context of Rag-1 and BLT hu-mice suggesting the possibility of developing a small animal model of HAM/TSP for testing groundbreaking therapies.
MAIT cells (CD8+CD161++TCR7.2++) are functionally impaired during chronic SHIV infection.
Authors: Murugesan Amudhan , Ibegbu Chris , Styles Tiffinay , Hicks Sakeenah , Sabula Micheal , Reddy Pradeep Babu Jagadeesh , Jones Andrew , Shankar Esaki Muthu , Amara Rama Rao , Velu Vijayakumar 
Published: January 2023

Abstract
Mucosa-associated invariant T-cells (MAIT) are abundant in humans and recognize bacterial ligands. Here, we have studied the distribution and function of MAIT cells during chronic SHIV infection using rhesus macaques (RM). Two groups of RM, healthy and SHIV infected were studied. lymphocytes from various tissues were analysed for MAIT (TCR7.2++ CD161++) cells using multicolor flow cytometry and characterized for their distribution, phenotype and function during chronic SHIV infection. Similar to human, we found significant fraction of (~2%) RM CD8 T cells co-express MAIT cell markers TCR7.2, CD161, IL-18R, CCR6 and display central memory (CCR7+CD45RA−) phenotype. The frequency of MAIT cells were decreased during chronic SHIV infection and tissue analysis showed a significant enrichment of MAIT cells in liver (~8%) and BAL (3%) than in blood (1%), spleen(0.5%), lymph node(0.13%) and gut (0.2%). Importantly, during chronic SHIV infection more than 80% of MAIT cells expressed T cell exhaustion marker PD-1 in blood and the level of expression was higher (&gt;95%) in tissue resident CD69+MAIT cells. These cells lack proliferating capacity (Ki-67) and cytokine production (IFN- g and IL-17) in the blood, suggesting their functional impairment. The preserved blood and gut MAIT cells correlate inversely with plasma viral RNA levels and associate directly with gut CD4 T cell levels, suggesting that CD4 help maintains MAIT cell frequencies in the gut. These data demonstrate that MAIT cells are decreased in blood and are functionally exhausted during chronic SHIV infection. Future studies focused on blocking the PD-1 pathway to retrive MAIT cell exhaustion during chronic SHIV/HIV infection may yield therapeutic benefit to HIV/SHIV infection.
Characterising ZBTB20 as a novel regulator of effector CD8 T cell longevity and differentiation
Authors: Sun Yanbo , Usherwood Edward J 
Published: January 2023

Abstract
During pathogen infection a T cell response is induced in order to control the infection. T cell differentiation can follow a variety of paths, including terminal differentiation to effector cells or differentiation to memory cells with stem cell-like self-renewal capacity. This process is known to be controlled in part by several transcription factors such as TCF-1, T-bet, eomesodermin, Blimp-1 and Bcl-6. Zbtb20, also known as HOF or DPZF, belongs to an evolutionarily conserved transcription factor family named BTB-ZF family. BTB-ZF proteins, including BCL-6, PLZF, BAZF and ZBTB20, play critical roles in a wide range of biological process including developmental events, cell cycle progression in normal and oncogenic tissues and maintenance of the stem cell pool. In the past decade, an emerging volume of literature has demonstrated that many BTB-ZF proteins are also key players in the development and function of lymphocytes and myeloid cells. Here we sought to examine if ZBTB20 affects T cell differentiation or function in response to infection by viruses or intracellular bacteria. We present data using both conditional deletion and overexpression strategies testing how zbtb20 affects the size, quality and memory potential of the pathogen-specific T cell response. This work has important implications for strategies to understand and enhance the T cell response to pathogens.
Crucial role of FOXO1 in inflationary CD8+ T-cell responses during persistent viral infection
Authors: Delpoux Arnaud , Michelini Rodrigo Hess , Verma Shilpi , Lai Chenyen , Omilusik Kyla D , Benedict Chris A , Hedrick Stephen M 
Published: January 2023

Abstract
Cytomegalovirus (CMV) establish persistent infection that induce the accumulation of virus-specific T-cells over time in a process called memory inflation. Although persistence of antigen (Ag) is considered essential, the molecular pathway for the inflationary T-cell development is poorly understood. Mainly, inflationary CD8 T-cells are KLRG1hi CD27−, but a low percentage of them are KLRG1lo CD27+, which are considered as their memory precursors. To study the role of FOXO1 in CD8 T cells during MCMV infection, we analyzed mouse bone marrow chimeras in which FOXO1 was specifically deleted in CD8 T cells. These mice were infected with MCMV-Δm157 strain, and the expansion and phenotype of inflationary was examined. The results revealed that the IE3 and M38 CD8 T-cell responses do not inflate in absence of FOXO1. Furthermore, with an absence of FOXO1, there were fewer Ag-specific CD8 T cells that produced both IFNγ and TNFα. Consistent with this lack of CD8 effector cells the mice were less able to control the virus in the spleen and the liver at day 6 after infection. Moreover, the FOXO1 KO Ag-specific CD8 T cells fail to up-regulate the memory associated transcription factors, TCF-1 and EOMES, correlating with a lower percentage of memory precursors. Then, we found that FOXO1 KO Ag-specific CD8 T cells display an anergic state and are prone to apoptosis. Finally, we delete FOXO1 at day 40 after infection, we showed that the FOXO1 KO Ag-specific CD8 T cells survive less efficiently and lose their memory characteristics as well as their recall capacities. Collectively, these results demonstrate an intrinsic role for FOXO1 in establishing and maintaining the inflationary memory program that is essential to forming long-lived effector and memory cells.
FCRL3 modulates the function of human thymic regulatory T cells
Authors: Kraus Zachary J , Agarwal Stuti , Dement-Brown Jessica , Tolnay Mate 
Published: January 2023

Abstract
Peripheral tolerance is achieved as the result of a delicate balance between inflammatory and tolerogenic signals. Regulatory T cells (Treg) are at the forefront in maintaining this balance, and external factors capable of modifying their suppressive function can be a powerful tool in future therapies for cancer and autoimmune disease. FCRL3 is a member of a novel family of antibody binding receptors expressed by specific human B cell and thymic Treg (tTreg) subsets that are reported to have altered suppressive function. Most importantly, overexpression of FCRL3 is strongly associated various autoimmune diseases. In particular, FCRL3 overexpression on Tregs is associated with more severe cases of rheumatoid arthritis. FCRL3 in B cells was shown to have dual signaling capacity; however no study addressed the functional role of FCRL3 in Treg. We used tTregs purified from human blood and pre-stimulated through FCRL3 to directly test the role of FCRL3 on Treg function using in vitro Treg suppression assays. We observed that engagement of FCRL3 increased Treg proliferation while reduced their suppressive activity, suggesting for the first time a direct link between FCRL3 and Treg function. TLR2 signaling has also been shown to repress the suppressive effect of human Tregs, therefore we tested possible integration with FCRL3 signaling. When TLR2 agonists were used together with FCRL3 pre-stimulation, we found indications of signal integration by tTreg downstream of FCRL3 and microbial sensing. We propose that FCRL3 is a novel regulator of Treg functionality, suggesting a mechanism for its association with autoimmune diseases.