Hai Qi

Hai Qi
Tsinghua University | TH · Department of Basic Medical Sciences

Ph.D.

About

118
Publications
18,467
Reads
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6,072
Citations
Citations since 2017
53 Research Items
3499 Citations
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Introduction
I am a scientist interested in creating new ways to improve human health by studying the immune system. My interests include humoral immune regulation and immune cell-cell interactions in different physiological and pathological settings. My approaches include mouse models, classical cell immunological methods, two-photon laser scanning microscopy, intravital imaging, and single-cell analyses.
Additional affiliations
January 2015 - present
Tsinghua University
Position
  • Professor
May 2009 - December 2014
Tsinghua University
Position
  • Professor (Associate)
June 2003 - April 2009
National Institute of Allergy and Infectious Diseases
Position
  • Fellow

Publications

Publications (118)
Article
Guiding immune cells to the center Germinal centers (GCs) are the site of antibody affinity maturation. The GC response fundamentally depends on contact-dependent signal exchange between antigen-specific T and B lymphocytes. Lu et al. uncovered a repulsive guidance system that inhibits GC recruitment and retention of T follicular helper (T FH ) cel...
Article
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The germinal centre (GC) reaction supports affinity-based B-cell competition and generates high-affinity bone-marrow plasma cells (BMPCs). How follicular T-helper (TFH) cells regulate GC selection is not clear. Using competitive mixed chimaera, we show here that, beyond the role in promoting TFH development, ICOSL (inducible T-cell co-stimulator li...
Article
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Germinal centres support antibody affinity maturation and memory formation. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, caus...
Article
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Generation of long-term antibody-mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen-specific T and B lymphocytes. In human X-linked lymphoproliferative disease and its gene-targeted mouse model, loss-of-function mutations in signalling lymphocyte activation molecule-associated protein (SAP, encoded...
Article
T follicular helper (TFH) cells play a crucial part in the development of humoral immunity by controlling the formation of, and the cellular reactions that occur in, germinal centres. Within these organized lymphoid tissue microstructures, B cells proliferate and somatically mutate to produce long-lived, high-affinity plasma cells and memory B cell...
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Microglial abnormalities may contribute to neurodevelopmental disorders. PTEN is implicated as a susceptibility gene for autism spectrum disorders and its germline ablation in mice causes behavioral abnormalities. Here we find postnatal PTEN deletion in microglia causes deficits in sociability and novel object recognition test. Mutant mice harbor m...
Article
The brain may sense, evaluate, modulate, and intervene in the operation of immune system, which would otherwise function autonomously in defense against pathogens. Antibody-mediated immunity is one arm of adaptive immunity that may achieve sterilizing protection against infection. Lymphoid organs are densely innervated. Immune cells supporting the...
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Durable antibody immunity depends on long-lived plasma cells (LLPCs) that primarily reside in the bone marrow (BM). However, due to LLPC rarity, it has not been possible to define their phenotypes or determine their heterogeneity. By single-cell mRNA sequencing, cytometry and a genetic pulse–chase mouse model, we show that IgG and IgM LLPCs display...
Preprint
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The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and “anatomical escape” characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines devel...
Article
Neuroimmunology is an interdisciplinary branch of biomedical science that emerges from the intersection of studies on the nervous system and the immune system. The complex interplay between the two systems has long been recognized. Research efforts directed at the underlying functional interface and associated pathophysiology, however, have garnere...
Article
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Background Prevalent single-cell transcriptomic profiling (scRNA-seq) methods are mainly based on the synthesis and enrichment of full-length double-stranded complementary DNA. These approaches are challenging to generate accurate quantification of transcripts when their abundance is low or their full-length amplifications are difficult. Results B...
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Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomi...
Article
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The germinal center (GC) is a self-organizing structure produced in the lymphoid follicle during the T-dependent immune response and is an important component of the humoral immune system. However, the impact of the special structure of GC on antibody production is not clear. According to the latest biological experiments, we establish a spatiotemp...
Article
Two and a half years into the COVID-19 pandemic, we have gained many insights into the human antibody response to the causative SARS-CoV-2 virus. In this Review, we summarize key observations of humoral immune responses in people with COVID-19, discuss key features of infection- and vaccine-induced neutralizing antibodies, and consider vaccine desi...
Preprint
The suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca ²⁺ -release chann...
Article
以变应性鼻炎(AR)为代表的变应性疾病严重影响患者生活质量,是影响人类健康的重大慢性疾病。20世纪以来全球AR患病率增长明显,不仅给患者个体造成身心伤害,亦对社会经济造成不良影响。本文概述了以AR为代表的变应性疾病的流行趋势、影响因素和我国的防治策略,提出在应对全球变应性疾病流行的复杂状况时,应全面认识人类个体健康、环境宜居性和地球健康三者间的紧密联系,从改善局部环境和缓解个体疾病入手,为解决人类生存的宏观问题提供微观路径和经验。.
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With the rapid emergence and spread of SARS-CoV-2 variants, development of vaccines with broad and potent protectivity has become a global priority. Here, we designed a lipid nanoparticle-encapsulated, nucleoside-unmodified mRNA (mRNA-LNP) vaccine encoding the trimerized receptor binding domain (RBD trimer) and showed its robust capability in induc...
Article
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Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here we reported that an Asian-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improve...
Article
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T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-inde...
Chapter
Follicular T-helper cells play a key role in orchestrating the germinal center response. Cellular dynamics revealed by intravital imaging have helped deepen our understanding of how follicular T-helper cells develop and function in vivo. Here we describe routine methods to image T-cell dynamics during germinal center responses. Methods for quantita...
Preprint
Full-text available
Many single cell RNA-seq applications aim to probe a wide dynamic range of gene expression, but most of them are still challenging to accurately quantify low-aboundance transcripts. Based on our previous finding that Tn5 transposase can directly cut-and-tag DNA/RNA hetero-duplexes, we present SHERRY2, an optimized protocol for sequencing transcript...
Article
One hundred years after the 1918 influenza pandemic, the world has seen another major outbreak on a global scale. This one is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), an enveloped positive-sense single-stranded RNA virus. According to the World Health Organization, as of June 17, 2021, there have been 176,693,988 conf...
Article
A primary immune response is initiated in secondary lymphoid organs. Virtual memory CD8+ T (TVM) cells are antigen-inexperienced T cells of a central memory phenotype, acquired through self-antigen–driven homeostatic proliferation. Unexpectedly, we find that TVM cells are composed of CCR2+ and CCR2− subsets that differentially elaborate a spectrum...
Article
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BCL6 is required for development of follicular T helper (Tfh) cells to support germinal center (GC) formation. However, it is not clear what unique functions programmed by BCL6 can explain its absolute essentiality in T cells for GC formation. We found that ablation of one Bcl6 allele did not appreciably alter early T cell activation and follicular...
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The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing eithe...
Article
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Antibody affinity maturation depends on positive selection in germinal centres (GCs) of rare B cell clones that acquire higher-affinity B cell receptors via somatic hypermutation, present more antigen to follicular helper T (TFH) cells and, consequently, receive more contact-dependent T cell help¹. As these GC B cells and TFH cells do not maintain...
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A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03384-8.
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SLAM family receptors are involved in humoral immune regulation. In this issue of JEM, Zhong et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20200756) provide evidence that these receptors collectively suppress germinal center reaction but promote production of antigen-specific antibodies.
Preprint
Full-text available
The development of an effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we present three chimpanzee adenovirus vaccines that express either the full-length spike (ChAdTS-S), or receptor-binding domain (RBD) with two different signal sequences (ChAdTS-RBD and ChAdTS...
Preprint
Full-text available
The presence of B lymphocytes in tumor tertiary lymphoid structures (TLSs) is an important prognostic indicator for different types of cancers. However, whether B cell responses in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here we report that a protective germline variant of human immunoglobulin heavy constant...
Article
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Germinal center (GC) formation is a critical step during T-dependent humoral immune responses. We report Death Associated Protein Kinase 2, a serine/threonine kinase, is rapidly induced in T cells following activation and plays an inhibitory role in T cell-mediated help for the GC formation. Specifically, T cells deficient in Dapk2 have an increase...
Preprint
Full-text available
Germinal center (GC) is a particular biological structure produced for affinity maturation in the lymphoid follicle during the T-dependent immune response and is an important component of the humoral immune system. However, the impact of morphological features of the GC on antibody production is not clear. According to the latest biological experim...
Article
Full-text available
It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activit...
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Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males1–3. However, the mechanisms underlying such sexual dimorphism are not well understood. Here we show that there are intrinsic differences between the B cells that produce germinal centres in male and female mice....
Article
Hai Qi describes a 2007 paper by Jason Cyster and colleagues that identified PD1 as a marker for T follicular helper cells.
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Dendritic cells (DCs) play key roles in Ab responses by presenting Ags to lymphocytes and by producing proinflammatory cytokines. In this study, we reported that DC-specific knockout of discs large homologue 1 (Dlg1) resulted in a significantly reduced capacity to mediate Ab responses to both thymus-independent and thymus-dependent Ags in Dlg1fl/fl...
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Follicular T‐helper (TFH) cells play a crucial role in three aspects of the germinal center (GC) response. They promote GC formation, arbitrate competition among GC B cells to determine the outcome of affinity maturation, and regulate GC output of memory and plasma cells to shape the long‐lived humoral immune memory. Of fundamental importance are d...
Article
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The B7-family inducible costimulator (ICOS) activates phosphoinositide-3 kinase (PI3K) and augments calcium mobilization triggered by the T-cell receptor (TCR). We surprisingly found that the entire cytoplasmic domain of ICOS is dispensable for its costimulation of calcium mobilization. This costimulatory function relies on the unique transmembrane...
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An IgG1 SNP enhances autoimmunity One common feature of autoimmune diseases like systemic lupus erythematosus (SLE) is the presence of high titers of self-reactive antibodies. These result in immune complexes, inflammation, and tissue pathology. Consequently, the checkpoints that normally keep immunoglobulin G (IgG)–positive autoreactive B cells in...
Data
Table S1. Differential Gene Expression between Pdcd1KI/KI and WT Tfh Cells. Related to Figure 6 GFP-transduced wildtype or Pdcd1KI/KI OT-II T cells were transferred into B6 mice (5 × 105 sorted GFP+ cells per mouse) together with 5 × 105 dsRed-expressing MD4 B cells, and the recipients were subcutaneously immunized with HEL-OVA. CXCR5hi OT-II T ce...
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Follicular T helper (Tfh) cells highly express the programmed cell death-1 (PD-1) molecule. Whereas inhibition of T cell receptor (TCR) signaling and CD28 co-stimulation is thought to be the primary mode of PD-1 functions, whether and how PD-1 regulates Tfh cell development and function is unclear. Here we showed that, when engaged by the ensemble...
Article
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Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM response...
Article
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Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM response...
Article
Lymphocytes have evolved sophisticated signaling amplification mechanisms to efficiently activate downstream signaling after detection of rare ligands in their microenvironment. B cell receptor microscopic clusters (BCR microclusters) are assembled on the plasma membrane and recruit signaling molecules for the initiation of lymphocyte signaling aft...
Article
Due to the apoptosis-prone nature of primary germinal center B (GCB) cells, it remains a huge challenge to dissect signals that guide their differentiation towards memory B cells and plasma cells in vitro. Here we show that the murine lymphoma cell line A20 resembles primary GCB cells in expression of GC-specific surface markers and the master tran...
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Immune cells called T cells help immune-system B cells mature to produce antibodies. This entails signalling between cells using the molecule dopamine [mdash] a surprising immunological role for this neurotransmitter.
Article
Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of af...
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Dynamic imaging analyses of antigen-specific T-B interactions in germinal centers have advanced our understanding of the molecular mechanisms underlying affinity maturation and provided a wealth of information about how follicular helper T cells function in vivo. Here we describe a routine method to visualize fluorescence protein-expressing, antige...
Article
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Follicular T helper (TFH) cells orchestrate the germinal center (GC) response locally. TFH localization in GCs is controlled by chemo-guidance cues and antigen-specific adhesion. Here. we define an antigen-independent, contact-dependent, adhesive guidance system for TFH cells. Unusual for amoeboid cell migration, the system is composed of transmemb...
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Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesi...
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Regulatory T (T reg) cells are essential for peripheral homeostasis and known to target and suppress dendritic cells (DCs). One important mechanism is through prolonged interaction between antigen-specific T reg cells and DCs that down-regulates the co-stimulatory capacity of DCs. However, the dynamics and TCR specificities of such T reg cell–DC in...
Article
During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential(1-4). Nevertheless, exhausted CD8(+) T cells can still contain viral replication in chronic infections(5-9), although the mechanism is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expres...
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The germinal center (GC) reaction underlies productive humoral immunity by orchestrating competition-based affinity maturation to produce plasma cells and memory B cells. T cells are limiting in this process. How B cells integrate signals from T cells and BCRs to make fate decisions while subjected to a cyclic selection process is not clear. In thi...
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We report the chemical synthesis of the first photo-activatable protein antigen that can be used to study antigen–antibody interaction mediated responses in B cells. This strategy facilitated fine tuning of the caged protein antigen to optimize its bioactivity and photochemical properties. One optimal molecule, HEL-K96NPE, was totally inert to hen...
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B cells that express the isotype-switched IgG-B cell receptor (IgG-BCR) are one of the driving forces for antibody memory. To allow for a rapid memory IgG antibody response, IgG-BCR evolved into a highly effective signalling machine. Here, we report that the positively charged cytoplasmic domain of mIgG (mIgG-tail) specifically interacts with negat...
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How follicular T-helper (Tfh) cells develop is incompletely understood. We find that, upon antigen exposure in vivo, both naïve and antigen-experienced T cells sequentially upregulate CXCR5 and Bcl6 within the first 24 h, relocate to the T-B border, and give rise to phenotypic Bcl6+CXCR5+ Tfh cells before the first cell division. CXCR5 upregulation...
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Chemokine-guided lymphocyte positioning in tissues is crucial for normal operation of the immune system. Direct, real-time manipulation and measurement of single-cell responses to chemokines is highly desired for investigating the cell biology of lymphocyte migration in vivo. Here we report the development of the first two-photon-activatable chemok...