bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of plasmacytoid dendritic cells in the delay of Th17 production during Bordetella pertussis infection in mice (MPF6P.738)
Authors: Wu Victoria , You Hana , Ferguson Ryan , Niknam Shahryar , Abramson Tzvia 
Published: January 2023

Abstract
Whooping cough, caused by Bordetella pertussis (Bp), is a highly contagious respiratory disease. Pertussis toxin (PTX) is largely responsible for extreme leukocytosis and chronic disease. Th17 cells have been implicated in host defense and control of mucosal pathogens, including Bp. Plasmacytoid dendritic cells (pDCs) have been shown to participate in Th17 commitment through secretion of IL-6. However, stimulation of pDCs through Toll-like receptor 7 leads to the secretion of IFN-α, a cytokine documented to inhibit Th17 differentiation. pDCs are activated during lung inflammation in response to pathogens, but their role during Bp infection is understudied. Using murine infection models of Bp and BpΔPTX (Bp strain devoid of PTX), we test the hypothesis that the functions of pDCs can manipulate the rise of Th17 cells during infection. Lung Th17 cells increase significantly in Bp-infected mice only by 10 days post-infection (p.i.), while lung pDCs emerged 2-3 fold at 5 days p.i. During the late rise in Th17 cells, the frequency of pDCs secreting IFN-α drops while those secreting IL-6 increase. In addition, blocking IFN-α production in mice results in an earlier increase in Th17 cells during infection. The recruitment and cytokine secretion of lung pDCs during infection with Bp correlate with the delayed Th17 responses, suggesting a role for pDCs in Th17 differentiation that may account for a longer-lasting disease.
Protective effector memory CD4+ T cells are generated from an early effector memory precursor (MPF6P.739)
Authors: Opata Michael , Carpio Victor , Ibitokou Samad , Obiero Joshua , Dillon Brian , Langhorne Jean , Stephens Robin 
Published: January 2023

Abstract
Effector memory CD4+ T cells (Tem) are the predominant memory subset in chronic infections such as malaria and tuberculosis. Tem respond quickly by making effector cytokines. Therefore, understanding their mechanism of generation and the role of persistent antigen is essential for vaccination strategies. The current paradigm of Tem generation is that they develop progressively from mature effector T cells in the contraction phase, however this remains to be established. In order to identify a precursor of Tem we identified three effector subsets with an Early CD127-CD62Lhi CD4+ memory precursor effector T cell (MPEC) population, and short-lived CD62Llo Teff (SLEC). In adoptive transfer experiments, we show the potential of Early Teff to diverge into either terminal Teff or memory cells depending on the environment, while mature Teff lose their memory potential, in contrast to the progressive differentiation model. Furthermore, we demonstrate that resting central memory T cells can become Tem in the absence of further stimulation. All three effector subsets protect immunocompromised animals, however, only Late Effector memory (TemL) improves both infection and pathology. Based on our data we propose an early decision point for generation of protective effector memory T cells, suggesting that memory development occurs in the early phase of activation. This work also suggests that TemL represent a correlate of immunity in chronic infection and can improve vaccine design studies.
Although the induction of INF-γ+ CD8 T cells by radiation-attenuated Plasmodium berghei sporozoites is TAP-independent, the recall of protective effector CD8 T cells during infection requires TAP machinery (MPF6P.740)
Authors: Pichugin Alexander , Steers Nick , De La Vega Patricia , Krzych Urszula 
Published: January 2023

Abstract
Multiple exposures of humans and laboratory rodents to radiation-attenuated Plasmodium sporozoites (γ-spz) induce sterile and long-lasting protection that is thought to be directed mainly to liver-stage antigens (LS-Ags). Although protection involves B cells and CD4 T cells, MHC class I-dependent liver IFN-γ+ CD8 T cells are the key effectors against LS-Ags. Recently several LS-Ags have been shown to induce protection in murine models; nevertheless, the mechanism of processing and presentation of LS-Ag to CD8 T cells has not been investigated. We tested liver CD8 T cell responses induced by Plasmodium berghei (Pb) γ-spz in TAP-/- mice to inquire whether processing/presentation of the exogenous LS-Ags was TAP-dependent or -independent. Immunization with Pb γ-spz induced proliferation and IFN-γ production by liver CD8 T cells. Also, TAP-/- CD8 T cells eliminated hepatocytes infected with Pb sporozoites in vitro. Despite these effector activities, Pb γ-spz immunized TAP-/- mice were not protected against sporozoite infection, mainly because liver CD8 T effector cells failed to produce IFN-γ in response to infectious sporozoite challenge. Our results demonstrate that although TAP-independent vacuolar pathway operates efficiently during immunization with γ-spz, the TAP-associated phagosomal-to-cytosol antigen processing mechanism appears to be required for effective recall of effector CD8 T cells during infection. The implications of these findings will be discussed.
Neutrophils are not a primary contributor to the early chemokine and cytokine cascade during Chlamydial infection (MPF7P.748)
Authors: Agugbuem Cemeka , Yeruva Venkat , Rank Roger 
Published: January 2023

Abstract
Chlamydia trachomatis is a common cause of tissue scarring, pelvic inflammatory disease, ectopic pregnancy, and infertility in women. A milieu of chemokines and cytokines contribute to the resultant pathology, directing the acute inflammatory response to mitigate infection with damaging consequences for the host. Yet, there are no reports on the cellular source of this chemokine and cytokine cascade during the initial stage of the host-pathogen interaction. We utilized a mouse model to determine whether neutrophils are a primary contributor to the chemokine/cytokine response during the initial development cycle (42- 48hrs) following intracervical inoculation with Chlamydia muridarum. Antibody depletion of neutrophils significantly increased the number of chlamydial inclusion forming units at 48 hours post infection and the recruitment of macrophages and natural killer cells to the infection site. Chemokine and cytokine mRNA expression at 36 hours after inoculation showed an increase in TNF-α, CXCL1 and CXCL2 and a decrease in IFN-γ in comparison to isotype control mice. Furthermore, we observed a slight increase TGFβ2, although not significant, in the neutrophil-depleted mice but we did not see major changes in IL-1β, CXCL10, CCL2, CCL4, and CCL5. Our findings suggest neutrophils are not a primary contributor to the early chemokine and cytokine cascade during chlamydial infection and that infected epithelial cells may be the primary source of this response.
Human mesenchymal stem/stromal cells prevent experimental autoimmune uveitis by inhibiting Th17 cells and by inducing IL-10-expressing B220+CD19+ cells (MUC7P.759)
Authors: Kim Mee Kum , Oh Joo Youn , Jeong Hyun Jeong , Ryu Jin Suk , Kim Dong Hyun , Lee Hyun Ju , Kim Tae Wan , Wee Won Ryang 
Published: January 2023

Abstract
Mesenchymal stem/stromal cells (MSCs) have the remarkable ability to protect tissues by modulating immune responses in various autoimmune diseases. We here investigated that systemic administration of MSCs might prevent development of experimental autoimmune uveitis (EAU) in mice. The study was conducted in conformance with the FASEB Statement of Principles for the use of animals in research and education. Analysis of the retina during the efferent phase revealed that a single intraperitoneal injection of human bone marrow-derived MSCs (hMSCs) at the time of immunization markedly protected the retina from inflammation-mediated damage and suppressed levels of innate and adaptive pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, IFN-γ, IL-17A, and IL-2 in the eye. Analysis of draining lymph nodes (DLNs) during the afferent phase showed that hMSCs significantly decreased the proportions of IL-17- or IFN-γ-expressing CD4+ T cells as well as levels of their cytokines, IL-17A and IFN-γ. The levels of IL-1β, IL-6, IL-12, and IL-23 were not decreased by hMSCs. However, hMSCs significantly increased the level of immunoregulatory cytokine IL-10 and markedly induced the population of IL-10+B220+CD19+ cells in DLNs. Together, data demonstrate that systemic administration of hMSCs attenuates EAU by inducing IL-10-secreting B220+CD19+ cells and by suppressing the Th1/Th17 immune responses.
Trojan T cell horse: TLR5 ligand-secreting T cells reshape the tumor microenvironment and exhibit enhanced antitumor activity (TUM2P.909)
Authors: Kaczanowska Sabina , Geng Degui , Tsai Alexander , Ochoa Augusto , Johnson Laura , Davila Eduardo 
Published: January 2023

Abstract
T cell responses are downregulated by the immunosuppressive tumor microenvironment. On the basis of previous studies demonstrating that Toll-like receptor (TLR) engagement on T cells augments their responses, we hypothesized that T cells engineered to secrete the TLR5 ligand flagellin would enhance T cell costimulation in the tumor environment and augment antitumor activity. Human T cells engineered to express the MART-1 TCR and secrete TLR5-ligand (TLR5-L) responded to lower tumor antigen levels resulting in increased proliferation, cytolytic activity and reversed tumor growth associated with prolonged mouse survival in a xenogeneic model. Treatment with TLR5-L-secreting T cells eradicated tumor in 40% of mice in a syngeneic model. Intratumoral secretion of TLR5-L by T cells reshaped the tumor microenvironment in part by inducing of a distinct chemokine/cytokine profile rendering it more immunogenic and permissive to T cell infiltration. Furthermore, tumor lysis by TLR5-L-producing T cells triggered the priming of endogenous tumor-reactive CD8 and CD4 T cells. Characterization of the cellular composition of the tumor and spleen revealed a reduction in MDSCs in the spleen and increased expression of MHC I in the tumor. This study demonstrates for the first time the ability to use T cells to deliver a TLR agonist to the tumor site and that intratumoral TLR5-L contributes to various processes involved in tumor regression.
Alterations in Kv1.3 channels in tumor infiltrated lymphocytes of patients with head and neck tumors. (TUM2P.913)
Authors: Chimote Ameet , Hajdu Peter , Filipovich Alexandra , Casper Keith , Conforti Laura 
Published: January 2023

Abstract
The progression of solid tumors, such as head and neck squamous cell carcinoma (HNSCC), is strongly dependent on the host immune system. Tumor infiltrating lymphocytes (TIL) are potent mediators of an anti-tumor response; however their function is attenuated in solid tumors. T cell effector functions like cytokine production and cytotoxicity are dependent on cytoplasmic Ca2+ which is regulated by ion channels. In human T cells, Kv1.3 channels are responsible for membrane hyperpolarization that allows the sustained Ca2+ influx necessary for effector functions, but their role in TILs is not understood. We hypothesize that Kv1.3 activity is decreased in TILs thereby contributing to their decreased functionality. We obtained tumor samples and matched peripheral blood (PB) from 6 patients with HNSCC. CD3+ TILs were separated by mechanical dissociation of tumors and negative selection. TILs were 99% viable and comprised of 57% CD4+ (85% TEM and 10% Treg) and 36% CD8+ cells. Electrophysiology revealed a 70% reduction in functional Kv1.3 channels in TILs as compared to PB CD3+ cells from paired patients. The Kv1.3 currents in the PBTs of cancer patients were similar to those of healthy donors. Furthermore, we observed a 40% reduction in the ion channel-dependent component of Ca2+ influx (measured bypassing the T cell receptor) in TILs. Overall, these data indicate that defective Kv1.3 and Ca2+fluxes in TILs could contribute to reduced immune surveillance in cancer.
Tim-3 is expressed by a majority of NK cells at periphery but not at tumor site in patients with advanced melanoma (TUM2P.919)
Authors: Sun Zhaojun , Fourcade Julien , Pagliano Ornella , Chauvin Joe-Marc , Sander Cindy , Kirkwood John , Kuchroo Vijay , Zarour Hassane 
Published: January 2023

Abstract
Tim-3 is a type I glycoprotein expressed by innate and adaptive immune cells. Tim-3 is an inhibitory receptor expressed by dysfunctional tumor antigen-specific CD8+ T cells of patients with advanced melanoma at periphery and in the tumor microenvironment. Tim-3 is also constitutively expressed by functional and mature NK cells in healthy donors (HD). The expression of Tim-3 on NK cells isolated from melanoma patients (MP) and its role in regulating NK functions have not been evaluated yet. To this end, we have investigated Tim-3 expression by NK cells in PBMCs isolated from HD and MP. In sharp contrast with HD, Tim-3 is upregulated by CD56bright as compared to CD56dim NK cells in PBMCs of MP. Upon stimulation with IL-12 and IL-18, NK cells in HD and MP upregulated Tim-3 expression and Tim-3high NK cells produced more IFN-γ than Tim-3neg, suggesting they are more functional. IFN-γ production increased upon NK stimulation with cytokines and Tim-3 ligand Galectin-9 and did not decrease upon Tim-3 blockade. In contrast to circulating NK cells, tumor-infiltrating NK cells (TINKs) are CD56dim in their large majority (&gt; 98%), and exhibit lower levels of Tim-3 expression. Collectively, our data show that Tim-3 is expressed by a majority of functional circulating NK cells in HD and MP but only a minority of TINK cells, suggesting that TINK may be less functional than their peripheral counterpart.
High density of cytotoxic and regulatory T lymphocytes in gastric cancers with microsatellite instability (TUM2P.920)
Authors: Kim Hyoung-Il , Park Chung-Gyu , Hyung Woo Jin 
Published: January 2023

Abstract
Background: the association between cancer phenotype and host immune response has rarely been evaluated in gastric cancer. We hypothesized that microsatellite instability (MSI) is associated with pattern of tumor infiltrating lymphocytes (TILs). Methods: we evaluated the status of MSI and subset of TILs in gastric cancer patients who received curative resection. The number of MSI-High and non-MSI-High were matched 1:3. The immunohistochemical staining with anti-CD3, CD4, CD8, Foxp3, and granzyme B were used to quantify the subset of TILs. Results: of the 98 carcinomas studied, 27 were MSI-High and 71 were non-MSI-High. Clinicopathologic profiles were comparable for both groups. The absolute number of CD3+ T-cells was not significantly different. MSI-High tumors carried significantly higher numbers of CD8+ T-cells than non-MSI-High tumors, suggesting favorable prognosis. Paradoxically, MSI-High tumors also contained higher numbers Foxp3+ T-cells and higher ratio of Foxp3+/CD4+ T-cells suggesting unfavorable prognosis. In subgroup analysis using T classification, distribution of TILs according to MSI type changed in CD8 and CD4 subsets. Conclusions: Microsatellite instable gastric cancers harbor distinctive distribution of subset of tumor infiltrating lymphocytes according to tumor progression.
PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection (TUM2P.881)
Authors: MacFarlane Alexander , Jillab Mowafaq , Plimack Elizabeth , Hudes Gary , Uzzo Robert , Litwin Samuel , Dulaimi Essel , Al-Saleem Tahseen , Campbell Kerry 
Published: January 2023

Abstract
In this study, we analyzed expression of numerous immune cell markers on fresh PBMC from 90 RCC patients preoperatively and 25 age-matched healthy controls by 10-color flow cytometry. Postoperative blood samples were also analyzed from 23 members of the RCC patient cohort. The most striking phenotypic immune biomarker in RCC patients was a significant increase in PD-1 expression on certain PBMC in a subset of patients. Increased PD-1 expression on CD14bright myelomonocytic cells, effector T cells, and NK cells correlated to disease stage. Importantly, we also observed that expression was significantly reduced on all cell types in virtually all patients within 2 weeks after surgical resection of the primary tumor. Based upon our results, we conclude that PD-1 expression on fresh peripheral blood leukocytes may provide a useful indicator of RCC disease progression. Furthermore, measuring PD-1 levels in peripheral blood may assist in identifying patients likely to respond to PD-1 blocking antibodies, and these therapies may be most effective before and immediately after surgical resection of the primary tumor, when PD-1 expression is most prominent. Finally, we conclude that long-term PD-1 blocking therapy after nephrectomy may only be effective in stage 3 and stage 4 patients that retain PD-1 expression, presumably maintained by the presence of residual metastatic tumor.
Alpha fetoprotein hypersensitizes human natural killer cells to interleukin-2-mediated activation (TUM2P.885)
Authors: Vujanovic Lazar , Stahl Elizabeth , Butterfield Lisa 
Published: January 2023

Abstract
Alpha fetoprotein (AFP) is an oncofetal antigen commonly produced by hepatocellular carcinomas (HCC). Multiple studies have shown that tumor-derived AFP (tAFP) has an immunosuppressive role on T, B and dendritic cells which may play a role in HCC pathogenesis. However, a direct tAFP effect on natural killer (NK) cells remains unclear. We examined the ability of cord blood-derived AFP (nAFP) and tAFP to modulate human NK cell activity in vitro. We show that tAFP and, in particular, nAFP hypersensitize healthy donor NK cells to interleukin-2 (IL-2)-mediated activation. Individual nAFP and tAFP treatments specifically induce IL-1β and IL-6 secretion by NK cells, but do not enhance their overall activation as measured by CD69 upregulation, type-1 cytokine secretion, tumor cell killing and proliferation. Interestingly, by the same assessments, NK cells simultaneously stimulated with AFP and IL-2 have a higher degree of activation than those activated with only IL-2. The observed synergism between AFP and IL-2 may be mediated by the ability of AFP to modulate IL-2 receptor signaling, as shown by the ability of AFP to upregulate CD25, and downregulate CD122 and CD132 on NK cells. Overall, these data show that nAFP and tAFP hypersensitize NK cells to IL-2-mediated activation. Defining the impact of circulating AFP on NK cells may be crucial to understand the NK cell functional deficits described in HCC patients, and for the development of an effective HCC-targeting immunotherapy.
The effects of key pro-inflammatory cytokines on influenza vaccine induced memory CD8+ T cell homeostasis (VAC2P.938)
Authors: Zhou Xin , Wang Chongkai , Swain Susan , Haynes Laura , Kuchel George , McElhaney Janet 
Published: January 2023

Abstract
There are accumulated evidences show that many age related immune defects are attributed to declined T lymphocyte helper and effector function involved CD4+ and CD8+ T cells. The lower efficacy of current influenza vaccine in aged people and other high risk population such as hospitalized patients cause need to develop more effective vaccine adjuvants which can significantly enhance vaccine mediated T cell immune response in response to influenza virus. We investigated the influenza live virus and vaccine induced pre-inflammatory cytokine secretion profile in human PBMCs, evaluated the effects of several key cytokines on vaccine induced T cell homeostasis. Our data show that IL-2, IL-6 and IL-17A can affect the flu vaccine induced human T cell homeostasis by enhancing the naïve T cell proliferation and differentiation as well as driving memory into effector CD8+ T cells through classic cytokine signaling transduction pathway. Our results will be able to help evaluate the efficacy of future possible vaccine adjuvant for developing better influenza vaccine compounds.
Induction of polyfunctional human memory T cells by Wnt pathway activation (VAC3P.949)
Authors: Chiu Yen-Ling , Sung Boyi , Joy Jaimy , Blankson Joel , Oelke Mathias , Schneck Jonathan 
Published: January 2023

Abstract
Polyfunctionality is a hallmark of protective immunity against pathogens and cancer. However, the molecular mechanisms governing the induction of polyfunctional T cells are not completely understood. We found that during antigen-driven expansion of human virus-specific T cells, Wnt pathway activation enhances the CD62L+, CD28+, and KLRG1- central memory T cell phenotype and promoted the generation of highly polyfunctional virus-specific T cells. Such effects are not only seen in influenza-specific responses but also in terminally differentiated CMV- and HIV-specific T cells. Mechanistically induction of polyfunctionality was independent of arresting antigen-specific cell expansion and is T cell-intrinsic. These findings provide the first evidence that Wnt pathway activation leads to polyfunctional antigen-specific memory human T cells responses and therefore have implications for treatment of chronic viral infections and cancer.
Defining the role of the alarmin IL-33 during the CD8 T cell effector response (VAC3P.958)
Authors: St. Rose Marie-Clare , Tsurutani Naomi , Adler Adam , Vella Anthony 
Published: January 2023

Abstract
ST2, the receptor for the alarmin IL-33, is expressed on CD8 T cells and both IL-33 and ST2 can optimize anti-viral CD8 T cell immune responses. Further, signaling through ST2 in combination with innate-derived cytokines such as IL-12 can induce TCR-independent production of IFN-gamma. We sought to understand the role of the IL-33/ST2 pathway during the effector CD8 T cell response elicited after immunization with CD134 and CD137 costimulatory agonists. ST2 is rapidly up-regulated on CD27+ effector CD8 T cells during the earliest phase of T cell re-activation, even before the up-regulation of other well-known T cell activation markers. Also, CD27+ST2+ CD8 T cells expressed increased cytokines compared to CD27-veST2+ CD8 T cells, and blockade of ST2 impeded the expression of those cytokines. Moreover, CD27+ST2+ CD8 T cells can kill EL4 tumor targets. Thus, ST2 seems to be marking effector CD8 T cells with the best capacity to exert effector functions. Upon TCR engagement, viable effector CD8 T cells rapidly up-regulate ST2, which facilitates the delivery of additional activation signals through IL-33 that further augment T cell activation. Based on these findings, we hypothesize that IL-33 may be one of the first signals that link T cell activation with the local stromal environment. Thus, direct targeting of the more highly functional ST2+ CD8 T cells may improve the outcome of T cell-based cancer immunotherapies.