FCRN MEDIATED MUCOSAL IMMUNITY AND SUBUNIT VACCINE DELIVERY

FcRn, the neonatal Fc receptor, is an MHC class I related molecule, functions as an IgG protector and transporter. Binding of IgG by FcRn exclusively occurrs at acidic pH, in correlation with the fact that FcRn mainly resides in acidic endosomes. Herein, we found an association of FcRn with invariant chain (Ii). The interaction was initiated within the endoplasmic reticulum by Ii binding to either the FcRn heavy chain alone or heavy chain-beta-2-microglobulin complex and appeared to be maintained throughout the endocytic pathway. The CLIP in Ii was not required for FcRn-Ii association. The interaction was detected in IFN--treated THP-1, epithelial and endothelial cells, and immature mouse DCs. A truncated FcRn without the cytoplasmic tail was unable to traffic to early endosomes; however, its location in early endosomes was restored by Ii expression. FcRn was detected in the late endosome/lysosome only in the presence of Ii or upon exposure to IFN-. In immature human or mouse DCs, FcRn was barely detected in the late endosome/lysosome in the absence of Ii. Taken together, the intracellular trafficking of FcRn is regulated by its intrinsic sorting information and/or Ii chain. Vaccine strategies to prevent invasive mucosal pathogens are being sought due to the fact that 90% of infectious diseases are initiated at mucosal surfaces. However, our ability to deliver an mucosal vaccine antigen for induction of the protective immunity is limited. FcRn mediates the transport of IgG across polarized epithelial cells. Taking advantage of this unique transfer pathway, I sought to delivery of antigens across mucosal barrier using IgG Fc fused proteins. It was demonstrated that intranasal immunization with a model antigen herpes simplex virus type-2 (HSV-2) glycoprotein gD fused with an IgG Fc fragment combination with CpG ODN adjuvant resulted in a complete protection of wild type, but not FcRn knockout mice that were intravaginally challenged with virulent HSV-2 186. The immunization induced efficient mucosal and systemic antibody as well as long lasting memory immune responses. These results are the first to demonstrate that the FcRn-IgG transcellular pathway may represent a novel mucosal vaccine delivery path against mucosal infections

Molecular Basis of the Differentiation and Function of Virus Specific Follicular Helper CD4+ T Cells

During viral infection, virus-specific follicular helper T cells provide important help to cognate B cells for their survival, consecutive proliferation and mutation and eventual differentiation into memory B cells and antibody-secreting plasma cells. Similar to Tfh cells generated in other conditions, the differentiation of virus-specific Tfh cells can also be characterized as a process involved multiple factors and stages, however, which also exhibits distinct features. Here, we mainly focus on the current understanding of Tfh fate commitment, functional maturation, lineage maintenance and memory transition and formation in the context of viral infection

The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection

Follicular helper T cells (TFH cells), known as the primary “helpers” of the germinal center (GC) reaction, promote the humoral immune response to defend against various pathogens. Under conditions of infection by different types of pathogens, many shared transcription factors (TFs), such as Bcl-6, TCF-1, and Maf, are selectively enriched in pathogen-specific TFH cells, orchestrating TFH cell differentiation and function. In addition, TFH cells also coexpress environmentally associated TFs as their conventional T cell counterparts (such as T-bet, GATA-3, or ROR-γt, which are expressed in Th1, Th2, or Th17 cells, respectively). These features likely indicate both the lineage-specificity and environmental adaption of the TFH cell responses. However, the extent to which the TFH cell response relies on these environmentally specific TFs is not completely understood. Here, we found that T-bet was specifically expressed in Type I TFH cells but not Type II TFH cells. While dispensable for the early fate commitment of TFH cells, T-bet was essential for the maintenance of differentiated TFH cells, promoting their proliferation, and inhibiting their apoptosis during acute viral infection. Microarray analysis showed both similarities and differences in transcriptome dependency on T-bet in TFH and TH1 cells, suggesting the distinctive role of T-bet in TFH cells. Collectively, our findings reveal an important and specific supporting role for T-bet in type I TFH cell response, which can help us gain a deeper understanding of TFH cell subsets

The Transcription Factor TCF1 Preserves the Effector Function of Exhausted CD8 T Cells During Chronic Viral Infection

The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells

A portrait of CXCR5(+) follicular cytotoxic CD8(+) T cells

CD8(+) T cells differentiate into multiple effector and memory subsets to carry out immune clearance of infected and cancerous cells and provide long-term protection. Recent research identified a CXCR5(+)Tcf1(+)Tim-3(-) subset that localizes in, or proximal to, B cell follicles in secondary lymphoid organs of mice, non-human primates, and humans, hereby termed follicular cytotoxic T (TFC) cells. With remarkable similarity to follicular helper T (TFH) cells, TFC differentiation is dependent on transcription factors E2A, Bcl6, and Tcf1, but inhibited by other regulators, including Blimp1, Id2, and Id3. This review summarizes the phenotype, function, and differentiation of this new subset. Owing to its follicular location and self-renewal capability, we propose immunotherapeutic strategies to target TFC cells to potentially treat certain cancers and chronic infections such as HIV-1

A Portrait of CXCR5+ Follicular Cytotoxic CD8+ T cells

CD8+ T cells differentiate into multiple effector and memory subsets to carry out immune clearance of infected and cancerous cells and provide long-term protection. Recent research identified a CXCR5+Tcf1+Tim-3− subset that localizes in, or proximal to, B cell follicles in secondary lymphoid organs of mice, non-human primates, and humans, hereby termed follicular cytotoxic T (TFC) cells. With remarkable similarity to follicular helper T (TFH) cells, TFC differentiation is dependent on transcription factors E2A, Bcl6, and Tcf1, but inhibited by other regulators, including Blimp1, Id2, and Id3. This review summarizes the phenotype, function, and differentiation of this new subset. Owing to its follicular location and self-renewal capability, we propose immunotherapeutic strategies to target TFC cells to potentially treat certain cancers and chronic infections such as HIV-1.This work was supported by Australian National Health and Medical Research Council (GNT1147709 to D.Y.), the National Key Research and Development Program of China (2017YFC0909003 to D.Y.), the amfAR Research Consortium on HIV Eradication (109327-59-RGRL to D. Y), the Shandong Provincial Natural Science Foundation (ZR2016YL013 to D.Y.) and Priority Research Program of Shandong Academy of Sciences (D.Y.). D.Y. is supported by the Bellberry-Viertel Senior Medical Research Fellowship and intramural funds from The Australian National University, Shandong Academy of Sciences and Renji Hospit

Differentiation and Function of Follicular CD8 T Cells During Human Immunodeficiency Virus Infection

The combination antiretroviral therapeutic (cART) regime effectively suppresses human immunodeficiency virus (HIV) replication and prevents progression to acquired immunodeficiency diseases. However, cART is not a cure, and viral rebound will occur immediately after treatment is interrupted largely due to the long-term presence of an HIV reservoir that is composed of latently infected target cells that maintain a quiescent state or persistently produce infectious viruses. CD4 T cells that reside in B-cell follicles within lymphoid tissues, called follicular helper T cells (TFH), have been identified as a major HIV reservoir. Due to their specialized anatomical structure, HIV-specific CD8 T cells are largely insulated from this TFH reservoir. It is increasingly clear that the elimination of TFH reservoirs is a key step toward a functional cure for HIV infection. Recently, several studies have suggested that a fraction of HIV-specific CD8 T cells can differentiate into a CXCR5-expressing subset, which are able to migrate into B-cell follicles and inhibit viral replication. In this review, we discuss the differentiation and functions of this newly identified CD8 T-cell subset and propose potential strategies for purging TFH HIV reservoirs by utilizing this unique population

Upregulated miR-96-5p inhibits cell proliferation by targeting HBEGF in T-cell acute lymphoblastic leukemia cell line

Introduction. microRNAs (miRNAs) are critical for tumorigenesis and progression of T-cell acute lymphoblastic leukemia (T-ALL). MiR-96-5p has been shown to play important roles in the development of many cancers, but its roles in T-ALL have yet not been studied. Materials and methods. miR-96-5p expression was detected in T-leukemic cells from peripheral blood of 30 patients with T-ALL using real-time quantitative PCR (RT-qPCR). TargetScan database was utilized to identify the target genes for miR-96-5p, and their target relationship was verified by western blot, dual luciferase reporter assay and RT-qPCR. The effects of miR-96-5p on the viability and proliferation of T-leukemic cells (Jurkat cells) were respectively determined using MTT and BrdU incorporation assays. Results. miR-96-5p presented low expression levels by qPCR in peripheral blood of T-ALL patients compared to healthy volunteers. Upregulated miR-96-5p by miR-96-5p mimic transfection markedly inhibited the viability and proliferation of Jurkat cells. Furthermore, miR-96-5p negatively regulated the expression of its target gene, HBEGF. The decreased viability and proliferation of Jurkat cells caused by miR-96-5p over-expression was suppressed after the introduction of HBEGF plasmid. Conclusions. The presented study showed that upregulation of miR-96-5p inhibited the viability and proliferation of Jurkat T-leukemic cells through suppressing HBEGF expression. Our study provides a novel sight for understanding the pathological mechanism of T-ALL and suggests that miR-96-5p may be a potential biomarker for the therapy and diagnosis of T-ALL

Generalized Global Ranking-Aware Neural Architecture Ranker for Efficient Image Classifier Search

Neural Architecture Search (NAS) is a powerful tool for automating effective image processing DNN designing. The ranking has been advocated to design an efficient performance predictor for NAS. The previous contrastive method solves the ranking problem by comparing pairs of architectures and predicting their relative performance. However, it only focuses on the rankings between two involved architectures and neglects the overall quality distributions of the search space, which may suffer generalization issues. A predictor, namely Neural Architecture Ranker (NAR) which concentrates on the global quality tier of specific architecture, is proposed to tackle such problems caused by the local perspective. The NAR explores the quality tiers of the search space globally and classifies each individual to the tier they belong to according to its global ranking. Thus, the predictor gains the knowledge of the performance distributions of the search space which helps to generalize its ranking ability to the datasets more easily. Meanwhile, the global quality distribution facilitates the search phase by directly sampling candidates according to the statistics of quality tiers, which is free of training a search algorithm, e.g., Reinforcement Learning (RL) or Evolutionary Algorithm (EA), thus it simplifies the NAS pipeline and saves the computational overheads. The proposed NAR achieves better performance than the state-of-the-art methods on two widely used datasets for NAS research. On the vast search space of NAS-Bench-101, the NAR easily finds the architecture with top 0.01\unicode{x2030} performance only by sampling. It also generalizes well to different image datasets of NAS-Bench-201, i.e., CIFAR-10, CIFAR-100, and ImageNet-16-120 by identifying the optimal architectures for each of them