bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiretrovial therapy changes circulating autoantibody profiles in patients chronically infected with human immunodeficiency virus 1 (P6197)
Authors: Meng Zhefeng , Amet Tohti , Byrd Daniel , Lan Jie , Yu Qigui 
Published: January 2023

Abstract
The emergence of severe liver injury in some patients chronically infected with human immunodeficiency virus 1 (HIV-1) during antiretroviral therapy (ART) presents a diagnostic dilemma. It is unclear whether liver injury is a direct result of drug side effects or a consequence of HIV-1-associated autoimmune responses. To investigate the effect of ART on the pattern of autoimmune responses in HIV-1-infected patients, we used a slide-based autoantigen array to profile circulating autoantibodies against a total of 84 autoantigens in HIV-1-infected patients on ART (n=16) and ART-naïve (n=14). Serum samples from 30 uninfected individuals were also included to obtain autoantibody background information. Compared to uninfected individuals, ART-naïve patients had IgG and IgM autoantibodies increased 2 folds or greater to 13 and 8 different autoantigens, respectively. Strikingly, ART profoundly suppressed autoimmune responses in HIV-1-infected patients, as only IgG autoantibodies against 2 autoantigens increased 2 folds or greater than that in uninfected subjects, and no IgM autoantibodies were increased. In addition, the titers of these 2 IgG autoantibodies in patients on ART were significantly lower than that found in ART-naïve patients. Conclusion: HIV-1 infection enhances circulating autoantibodies that can be significantly suppresed by ART, and liver damage in patients on ART is most likely due to drug side effects rather than autoimmune responses.
HIV-1 infection induces a novel B cell response against HERV-K (HML-2) TM protein (P6209)
Authors: Michaud Henri-Alexandre , de Mulder Miguel , SenGupta Devi , Deeks Steven , Martin Jeffrey , Pilcher Christopher , Hecht Frederick , Sacha Jonah , Nixon Douglas 
Published: January 2023

Abstract
The presence of HERV-K (HML-2) mRNA in plasma and a corresponding specific T cell response during HIV-1 infection is well-documented. We hypothesized that HIV-1 also induces a specific HERV-K (HML-2) EnvelopeBcell response due to the expression of envelope protein on the infected cell surface. This led to the concept that HERV-K (HML-2) Env could be used as an HIV-1 Associated Neo Antigen (HANA) to target infected cells. We showed that the humoral response against HERV-K (HML-2) Env is restricted to two sequences on each envelope sub-unit, the surface unit (SU) and transmembrane (TM) proteins. During HIV-1 infection, we observed an increase of the anti-TM antibody titer and a decrease of the anti-SU antibody titer. Interestingly, we found that HIV-1-infected elite controllers had high titers of anti-TM antibodies compared to HIV-1 infected patients on effective HAART or healthy uninfected donors. We showed that TM is preferentially transactivated and expressed on the cell surface in HIV-1 infected cells. Using HA-137, a human anti-TM antibody, we showed that TM protein is preferentially expressed in the myeloid cell subset as well as in a distinct T cell subset. These findings highlight the crucial role of the monocyte/macrophage lineage in the induction of the anti-HERV-K (HML-2) TM Bcell response.This study suggests that the anti-TM humoral response may play a role in HIV-1 pathogenesis and could provide a new tool for immunotherapeutic strategies.
Host correlates distinguish low-risk and high-risk HIV-1 disease progression in HLA-B*5701 individuals (P6169)
Authors: Raposo Andre , Abdel-Mohsen Mohamed , Hecht Frederick , Pilcher Christopher , Pillai Satish , Nixon Douglas 
Published: January 2023

Abstract
HIV-1-infected individuals with HLA-B*57 alleles progress slowly to disease, in part due to restricted CD8+ T cell responses. However, some HLA-B*57 individuals progress faster to disease. We hypothesized that additional host correlates may explain the risk of disease progression. PBMC from six HLA-B*5701 patients were analyzed longitudinally and divided into high-risk and low-risk progressors based on CD4 counts at baseline. We developed a custom made Taqman array to measure mRNA expression of 34 anti-HIV-1 restriction factors. We named the overall gene expression as Cumulative Restriction or CuRe score. T cell activation, viral load, T cell counts and plasma sCD14 were also determined for all patients at all time-points. The CuRe score was significantly increased in high-risk progressors (p&lt;0.0001), with particular increases of APOBEC3F, APOBEC3G, tetherin, SAMHD1 and interferon-inducible genes. CuRe score correlated with viral load only in low-risk progressors (R&gt;0.60, P&lt;0.001). T cell activation was significantly elevated in high-risk progressors (p&lt;0.05), and correlated with a decline in CD4+ T cell counts (Spearman R=-0.92, P&lt;0.0001). Plasma sCD14 was significantly elevated in high-risk progressors, and correlated with CuRe score (R=0.79, P&lt;0.001). In our study, we show that combining a multiple gene expression array of anti-HIV-1 restriction factors and immunological parameters provide important measures of risk for disease progression in HLA-B*5701 individuals.
Human T cell lifespan (P1284)
Authors: Réu Pedro , Mold Jeff , Michaelsson Jakob , Salehpour Mehran , Frisen Jonas 
Published: January 2023

Abstract
In humans, the lifespan and turnover of T cells have been debated for almost half a century. Until now, the analysis of T lymphocyte turnover have been primarily approached through short term labelling studies and nucleotide analogue incorporation. While much has been gained from these endeavours, there is still considerable debate about the half live of the different T lymphocyte subsets and it is apparent that neither approach alone can give the necessary information to reach a conclusive result. Taking advantage of the decreasing concentration of 14C in the atmosphere since the cold war, we have retrospectively assessed the birth date of the different T cell populations in the blood of healthy adult humans.
Transcription factor Bach2 regulates naïve T-cell homeostasis and functional maturation of CD8 T-cell memory (P1309)
Authors: Kim Eui Ho 
Published: January 2023

Abstract
The transcriptional repressor Bach2 is considered as a B cell-specific transcription factor that maintains B cell identity by opposing terminal differentiation to plasma cells. Here, we show that Bach2 is expressed in CD8 T cells and the level of expression depends upon the cellular differentiation state. Bach2 is highly expressed in naïve and central memory T cells (TCM), but the more terminally differentiated effector cells and effector memory T cells (TEM) expressed low levels of Bach2. A larger fraction of CD8 T cells from Bach2-deficient (Bach2-/-) mice displayed the activated CD44HI phenotype and produced cytokines such as IFN-γ. Following an acute viral infection, Bach2-/- CD8 T cells showed normal clonal expansion and effector differentiation. However, without Bach2, effector to memory transition was markedly impaired. A substantially larger fraction of Bach2-/- memory CD8 T cells displayed the senescent KLRG1HI/CD127LO/CD27LO phenotype, with a marked reduction in the numbers of TCM cells. Functionally, Bach2-/- memory CD8 T cells produced lower levels of IFN-γ, TNFα and IL-2 but expressed higher levels of granzyme B, compared to WT. Thus, we have identified novel roles for Bach2 in maintaining naïve CD8 T-cell quiescence, promoting effector to memory transition and steering functional maturation of memory CD8 T cells, and development of TCM cells. These findings have improved our understanding of the transcriptional regulation of naïve and memory T-cell homeostasis.
ITK regulates the dynamics of CD8+ T cell homeostatic proliferation in lymphopenic environment (P1296)
Authors: Huang Weishan , Huang Fei , August Avery 
Published: January 2023

Abstract
Tec family kinase ITK is an essential regulator of T cell development and function. The absence of ITK leads to spontaneous acquisition of innate memory phenotype (IMP) in CD8+ T cells, shown to be induced by bystander-derived IL-4. CD8+ T cells undergone homeostatic proliferation (HP) in lymphopenic conditions share similar memory markers with IMP CD8+ T cells. To examine the role of ITK during CD8+ T cell HP, we compared naïve CD8+ T cells from WT and Itk-/- OTI-Rag-/- transgenic mice. We found that they had similar CD44loCD122- naïve phenotype, but naïve Itk-/- T cells exhibited increased Eomes, KLF2, FoxO3, Bim, Blimp-1 and decreased Bcl-6 mRNA expression. When transferred into lymphopenic Rag-/- recipients, Itk-/- naïve CD8+ T cells exhibited rapid early expansion, giving rise to &gt; 10 fold expansion over that of WT CD8+ T cells by 10 days post-transfer, which was followed by massive retraction with failure to sustain a plateau as seen in WT. The absence of ITK during HP resulted in defects in expression of cytokine receptors and Bcl-2, accompanied by enhanced apoptosis and Fas expression. These data indicate an important role of ITK in regulating the dynamics and maintenance of CD8+ T cells during HP, likely by regulating the expression of cytokine receptors required for sustained survival of these cells. This work suggests that targeting the ITK pathway may allow manipulation of CD8+ T cell number and function in lymphopenic conditions due to infection or irradiation.
Immune mechanisms mediated by Salmonella in ameliorating airway inflammation (P6031)
Authors: Sparwasser Tim , Ganesh Venkateswaran , Baru Mannan 
Published: January 2023

Abstract
Epidemiological data suggest protection from allergic diseases when exposed to infectious agents during early stages of life. As allergies are mainly characterized as an unchecked Th2 response, modulation of the immune responses by pathogens have been considered to be a major factor in mediating the protection. Recent evidences implicate a key role staged by immuno-regulatory mechanisms induced upon infection in ameliorating these allergic disorders. A longitudinal study had demonstrated the reduced frequency and incidence of asthma in children, who had a prior infection from Salmonella typhi. A subsequent investigation demonstrated reduced airway inflammation in mice infected with Salmonella; however the mechanism still remained obscure. In this study, we aimed to delineate the potential mechanisms induced upon Salmonella typhimurium infection which resulted in the amelioration of allergic airway inflammation in mice. We report a significant increase in CD11b+ Gr1+ myeloid cell population in those mice that had been infected with Salmonella. Using in vitro and in vivo analysis we suggest that these myeloid cells could potentially ameliorate airway inflammation by affecting the stability of Th2 cells. In contrast to our initial hypothesis, regulatory T cells were not involved in the protective effect of salmonella infection.
Commensal bacteria induce a barrier protective response to prevent sensitization to food allergens (P6037)
Authors: Feehley Taylor , Stefka Andrew , Tripathi Prabhanshu , McCoy Kathy , Mazmanian Sarkis , Seo Goo-Young , Theriault Betty , Antonopoulos Dionysios , Chang Eugene , Nagler Cathryn 
Published: January 2023

Abstract
Environmentally-induced alterations in the commensal microbiome have been implicated in the increasing prevalence of food allergy. We found that antibiotic treatment of neonatal mice leads to reduced proportions of regulatory T cells(Tregs) in the colonic lamina propria(LP), impaired production of intestinal IgA, and elevated peanut (PN) specific IgE/IgG1 in response to sensitization. Selective colonization of gnotobiotic mice linked the Treg/IgA inducing capacity to a consortium of bacteria within the Clostridia class. Introduction of either a conventional SPF microbiota or a mixture of Clostridia strains to antibiotic-treated mice restored the Treg and IgA compartments and blocked the induction of a food allergic response. Clostridia colonized gnotobiotic mice displayed increased expression of IL-23 and IL-22 in the colonic LP compartment and the induction of anti-microbial REG3β expression in the epithelium. Collectively, these results suggest that the maintenance of oral tolerance to dietary antigens relies on bacterial populations that induce a barrier protective response, which includes activation of the IL-23/IL22 axis and the expansion of intestinal Tregs and IgA secreting B cells. Our findings hold promise for the development of approaches to prevent or treat food allergy based on modulation of the composition of intestinal microbiota.
Respiratory syncytial virus infection of infant mice disables regulatory T cells with loss of protection from allergic airway disease (P6005)
Authors: Krishnamoorthy Nandini , Khare Anupriya , Oriss Timothy , Raundhal Mahesh , Morse Christina , Moore Martin , Peebles R.Stokes , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
Immune tolerance is established early in life beginning in utero. Tregs play a critical role in this process and protect from allergic disease. Although studies have shown a direct correlation between infection by RSV early in life and the risk of development of asthma in adult life, the underlying immune mechanism was not well understood. Towards this goal, we adopted a murine model of maternal transfer of tolerance to the model allergen Ovalbumin (Ova) in infant mice and studied the impact of recurrent RSV infection on tolerance to Ova. We show that infant mice previously tolerized to Ova via their mother’s milk, upon RSV infection, lose tolerance and mount characteristic features of allergic asthma when subsequently challenged with Ova. On the other hand, uninfected tolerized mice did not mount an immune response demonstrating preservation of tolerance. The cause for breach of tolerance in RSV-infected infant mice was found to be the virus’ ability to increase GATA-3 expression and IL-13 production in Foxp3+ Tregs. The Tregs from RSV infected mice had impaired suppressive function. Thus, by promoting Th2 inflammation, RSV interferes with the function of Tregs such that tolerance to an allergen is compromised. Interestingly, treatment of mice with the mucosal adjuvant CpG ODN prevented a switch in Treg phenotype. Our findings highlight a deleterious effect of viral infections in infancy on the immune system, which increases the risk for allergic responses later in life.
The mechanisms of non-depleting YTS177 anti-CD4 monoclonal antibody in controlling ovalbumin-induced asthmatic responses (P6017)
Authors: Kuo Ming-Ling , Wu Cheng-Jang , Lin Chun-Yen 
Published: January 2023

Abstract
Bronchial asthma is an emerged chronic inflammatory disorder of the airway characterized by airway hyperresponsiveness (AHR), pulmonary eosinophilia, elevated serum immunoglobulin (Ig) E, and dysregulated T helper (Th) 2 cytokines. It is becoming urgent to identify target molecules for the preventive and therapeutic purpose. Non-depleting YTS177 anti-CD4 monoclonal antibody (MoAb) has been used to induce immunotolerance in allograft transplantation through antigen-specific Treg cells. This study aims for determining whether YTS177 MoAb is able to inhibit the ovalbumin (OVA)-induced allergic inflammation in an asthmatic murine model. The injection of YTS177 MoAb before and after OVA-sensitization was able to suppress AHR, pulmonary eosinophilia, OVA-specific IgE synthesis, and the production of Th2 cytokines from OVA-activated splenocytes. YTS177 MoAb inhibited the proliferation of DO11.10 CD4+ T cells upon in vivo OVA-stimulation as well. Moreover, YTS177 MoAb-treatment sustained the protein levels of anergy factors, p27kip1 and Cbl-b, and inhibited IL-2 production and cell cycle progression in activated T cells in vitro. The tolerance status might be built on YTS177 MoAb-induced CD4 down regulation and raft dissociation through clathrin-dependent manner. Collectively, YTS177 MoAb binding causes CD4 internalization that further perturbs T cell receptor signaling and ultimately results T cell unresponsiveness.
The role of Eos in T cell function (P1059)
Authors: Rieder Sadiye , Shevach Ethan 
Published: January 2023

Abstract
Eos, an Ikaros family transcription factor, is preferentially expressed in T regulatory cells (Tregs). Although previous studies have demonstrated that the elimination of Eos by siRNA in Tregs resulted in the loss of their suppressive function both in vitro and in vivo, Tregs from mice with a global deletion of Eos suppress normally in vitro and in the IBD model in vivo. While non-activated T conventional (Tconv) cells fail to express Eos, Eos expression is rapidly upregulated following TCR activation in vitro. TCR activated Tconv cells from Eos deficient (-/-) mice proliferate poorly, but make normal amounts of IL-2. The diminished proliferative response is secondary to a defect in the upregulation of CD25 that is accompanied by a decrease in p-STAT5 and p-S6 levels. Surprisingly, Eos-/- mice develop more severe EAE compared to wild type (WT) mice. Mixed chimeras between WT and EOS-/- bone marrow donors also develop very severe EAE. A greater number of Eos-/- CD4+ T cells than WT CD4+ T cells can be detected in the CNS and they produce higher levels of IL-17 than WT CD4+ T cells. Increased IL-17 production by Eos-/- CD4+ T cells correlates with their defect in IL-2 signaling. While WT Tregs can be detected in the CNS of the chimeric mice, Eos-/- Tregs are not detectable. These studies raise the possibility that Eos negatively regulates the production of IL-17 in Tconv, and may also play an important role in the migration of Tconvs and Tregs.
Exosomes represent a novel mechanism of regulatory T cell suppression (P1079)
Authors: Steinkamp Heidi , Delgoffe Greg , Frase Sharon , Castellaw Ashley , Vignali Dario 
Published: January 2023

Abstract
Regulatory T cells suppress via a variety of mechanisms, both contact-dependent and -independent mechanisms. These is some controversy as to which mechanisms play more dominant roles during various disease states as well as maintenance of immune homeostasis. Our laboratory has found that regulatory T cells secrete exosome-like vesicles that are 20 to 50 nm in diameter. Membrane vesicles have been shown to mediate communication amongst immune cells, but they also mediate communication between immune cells and cancer cells and between and immune cells and pathogens. Membrane vesicles mediate physiologic changes in recipient cells by initiating cellular signaling events following receptor binding, or via uptake and integration of vesicular cargo, which can include receptors, enzymes, cytokines, chemokines and genetic material. We have found that functional regulatory T cell membrane vesicles mediate suppression of conventional CD4+ T cells, whereas resting regulatory T cell and conventional T cell vesicles do not. Furthermore, we have found that 293F cells package overexpressed immunosuppressive cytokines into exosomes following transfection. Taken together these data suggest that exosome-like vesicles represent a bridge between contact dependent and independent regulatory T cell suppression.
Dual regulation of CD8+ T cell and NK cells following systemic cancer immunotherapy (P1087)
Authors: Alvarez Maite , Sckisel Gail , Bouchlacka Myriam , Murphy William 
Published: January 2023

Abstract
NK-CD8 T cell regulation has been demonstrated in viral infection models. It is believed that NK cells regulate CD8 T cells to prevent exacerbated activation resulting in pathological effects. Current immunotherapy regimens use immunostimulation with blockade of negative regulators to achieve optimum antitumor effects. We observe that NK and CD8 T cells play dual roles in their concurrent regulation following systemic administration of IL2 and αTGFβ as the depletion of either population resulted in a higher expansion of the other. This data indicates a possible cytokine competition between both NK and CD8 T cell compartments. However, antigen nonspecific bystander CD8 T cells were particularly enhanced after NK depletion whereas CD4 T cells were not affected. Therefore, this data suggests a possible elimination of CD8 T cells after NK activation which is FasL-dependent as Fas expression is upregulated on CD8 T cells after NK depletion. This mechanism is not mediated by perforin because the IL2 treatment of perforin-deficient mice resulted in a higher CD8 T cell expansion after NK cell depletion. In conclusion, this study illustrates the existence of an NK-CD8 T cell regulation in an antigen-nonspecific stimulation model which demonstrates a tight regulation between adaptive and innate immune responses. Further, the study demonstrates the potential efficacy of increasing antitumor responses by concurrent application of immunostimulation with blockade of negative regulators.
TLR2 signaling in epithelial cells initiates sterile tissue inflammation through recruitment of NK cells (P1089)
Authors: Kim Hye Jeong , Lee Jong Soo , Kim Ahra , Koo Sumi , Cha Hee Jeong , Kwon Byoung S. , Mittler Robert , Cho Hong R. , Kwon Byungsuk 
Published: January 2023

Abstract
It is well recognized that damage-associated molecular patterns (DAMPs) released from damaged kidney cells initiate post-ischemic inflammation, an essential step in the progression of kidney ischemia-reperfusion injury. However, the mechanism that coordinates this highly specific process in the ischemic kidney remains to be clarified. We report here that endogenous TLR2 ligands released from ischemic TECs induce expression of CCR5 chemokines in an autocrine manner, thereby promoting recruitment of NK cells. By implantation of CD137L-/- TECs into the kidney capsule of TLR2-/- mice and vice versa, we further show that TLR2-mediated recruitment of NK cells is an uncoupled event occurring independently of CD137L signaling in TECs and sufficient to result in kidney ischemia-reperfusion injury (IRI) by inducing subsequent recruitment of neutrophils that is dependent upon CD137L signaling in TECs. Therefore, our findings identify TECs as not only a target for kidney damage but also a master regulator that plays a central role in initiation and amplification of acute sterile inflammation inflicting kidney IRI. Clinically important, the signaling pathway of innate receptors in epithelial cells may therefore represent a good target for blocking acute sterile inflammation occurring as a result of tissue damage, including kidney IRI.
Detecting genuine regulatory relationships among transcription factors, miRNAs and target genes post influenza virus infection (P1091)
Authors: Miao Hongyu 
Published: January 2023

Abstract
The development of Systems Biology approaches has provided unprecedented opportunities for researchers to gain novel and deeper insights into biological mechanisms. In particular, Systems Biology methods have been proposed to identify gene regulatory relationships based on high-throughput omics data in the infectious disease setting. However, successful applications of the Systems Biology approaches in experimental studies have been hampered by two problems: first, post-transcriptional regulation is usually missing in previous modeling work; second, many approaches are purely data-driven and thus could have a high false positive rate in predicting regulatory relationships. In this study, we propose a new framework for detecting genuine regulatory relationships by exploiting both available expert knowledge and time-course expression data of transcription factors, miRNAs and target genes. The regulatory relationships are explicitly anchored to a set of potential interactions and then selected by rigorous quantitative methods such as DBN and LASSO. We apply our method to influenza virus infection in human and predict the target genes regulated by each transcription factor and miRNA with the highest potential.