Xiaoping Zhong

Overview:

The immune system protects the host from microbial infection but can cause diseases if not properly controlled. My lab is interested in the receptor signaling mediated regulation of immune cell development and function as well as the pathogenesis and treatment of autoimmune diseases and allergies.

We are currently investigating the roles diacylglycerol kinases (DGKs) and TSC1/2-mTOR play in the immune system. DGKs are a family of ten enzymes that catalyze the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), Both DAG and PA are important second messengers involved signaling from numerous receptors. While we expect DGKs to perform important roles in development and cellular function by modulating DAG and PA levels, the physiologic functions of DGKs have been poorly understood. Using cell line models and genetically manipulated mice, we have demonstrated that DGKα and ζ isoforms play critical roles in: T cell development, activation, and anergy by regulating T cell receptor signaling; FcεRI signaling and mast cell function; and Toll-like receptor signaling and innate immune responses.

Research areas that we are actively pursuing include:
1. The mechanisms that control T cell maturation, activation
and self-tolerance.
2. NKT cell development and function.
3. Thymic epithelial cells and thymic development, function, and involution.
4. Regulation of Toll-like receptor signaling and innate immunity. 
5. The pathogenesis and treatment of autoimmune hepatitis. 
6. Mast cell development and function.
7. The pathogenesis and immunotherapy for peanut allergy.

Positions:

Professor of Pediatrics

Pediatrics, Allergy and Immunology
School of Medicine

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

First Medical College in Guangzhou (China)

Ph.D. 1997

Duke University

Grants:

Duke Research Training Program for Pediatricians

Administered By
Pediatrics, Infectious Diseases
Awarded By
National Institutes of Health
Role
Training Faculty
Start Date
End Date

Targeting apoptotic caspases to enhance cancer radiotherapy

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Research Training in Allergy and Clinical Immunology

Administered By
Pediatrics, Allergy and Immunology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Regulating peripheral T cell tolerance

Administered By
Pediatrics, Allergy and Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

TSC1-mTOR signaling and T cell tolerance

Administered By
Pediatrics, Allergy and Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Development and Evaluation of a Novel Mouse Model of Asphyxial Cardiac Arrest Revealed Severely Impaired Lymphopoiesis After Resuscitation.

Background Animal disease models represent the cornerstone in basic cardiac arrest (CA) research. However, current experimental models of CA and resuscitation in mice are limited. In this study, we aimed to develop a mouse model of asphyxial CA followed by cardiopulmonary resuscitation (CPR), and to characterize the immune response after asphyxial CA/CPR. Methods and Results CA was induced in mice by switching from an O2/N2 mixture to 100% N2 gas for mechanical ventilation under anesthesia. Real-time measurements of blood pressure, brain tissue oxygen, cerebral blood flow, and ECG confirmed asphyxia and ensuing CA. After a defined CA period, mice were resuscitated with intravenous epinephrine administration and chest compression. We subjected young adult and aged mice to this model, and found that after CA/CPR, mice from both groups exhibited significant neurologic deficits compared with sham mice. Analysis of post-CA brain confirmed neuroinflammation. Detailed characterization of the post-CA immune response in the peripheral organs of both young adult and aged mice revealed that at the subacute phase following asphyxial CA/CPR, the immune system was markedly suppressed as manifested by drastic atrophy of the spleen and thymus, and profound lymphopenia. Finally, our data showed that post-CA systemic lymphopenia was accompanied with impaired T and B lymphopoiesis in the thymus and bone marrow, respectively. Conclusions In this study, we established a novel validated asphyxial CA model in mice. Using this new model, we further demonstrated that asphyxial CA/CPR markedly affects both the nervous and immune systems, and notably impairs lymphopoiesis of T and B cells.
Authors
Wang, W; Li, R; Miao, W; Evans, C; Lu, L; Lyu, J; Li, X; Warner, DS; Zhong, X; Hoffmann, U; Sheng, H; Yang, W
MLA Citation
Wang, Wei, et al. “Development and Evaluation of a Novel Mouse Model of Asphyxial Cardiac Arrest Revealed Severely Impaired Lymphopoiesis After Resuscitation.J Am Heart Assoc, vol. 10, no. 11, June 2021, p. e019142. Pubmed, doi:10.1161/JAHA.120.019142.
URI
https://scholars.duke.edu/individual/pub1483030
PMID
34013738
Source
pubmed
Published In
Journal of the American Heart Association
Volume
10
Published Date
Start Page
e019142
DOI
10.1161/JAHA.120.019142

iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.

Authors
Wu, J; Yang, J; Yang, K; Wang, H; Gorentla, B; Shin, J; Qiu, Y; Que, LG; Foster, WM; Xia, Z; Chi, H; Zhong, X-P
MLA Citation
Wu, Jinhong, et al. “iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.J Clin Invest, vol. 127, no. 11, 1 Nov. 2017, p. 4216. Pubmed, doi:10.1172/JCI98066.
URI
https://scholars.duke.edu/individual/pub1284502
PMID
29091076
Source
pubmed
Published In
J Clin Invest
Volume
127
Published Date
Start Page
4216
DOI
10.1172/JCI98066

Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1.

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells.
Authors
Zhang, S; Li, L; Xie, D; Reddy, S; Sleasman, JW; Ma, L; Zhong, X-P
MLA Citation
Zhang, Shimeng, et al. “Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1.Front Immunol, vol. 12, 2021, p. 620437. Pubmed, doi:10.3389/fimmu.2021.620437.
URI
https://scholars.duke.edu/individual/pub1482064
PMID
33936036
Source
pubmed
Published In
Frontiers in Immunology
Volume
12
Published Date
Start Page
620437
DOI
10.3389/fimmu.2021.620437

Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals.

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
Authors
Tao, H; Pan, Y; Chu, S; Li, L; Xie, J; Wang, P; Zhang, S; Reddy, S; Sleasman, JW; Zhong, X-P
MLA Citation
Tao, Huishan, et al. “Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals.Nat Commun, vol. 12, no. 1, Apr. 2021, p. 2029. Pubmed, doi:10.1038/s41467-021-22162-8.
URI
https://scholars.duke.edu/individual/pub1477802
PMID
33795689
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
2029
DOI
10.1038/s41467-021-22162-8

Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development.

Expression of tissue-restricted antigens (TRAs) in thymic epithelial cells (TECs) ensures negative selection of highly self-reactive T cells to establish central tolerance. Whether some of these TRAs could exert their canonical biological functions to shape thymic environment to regulate T cell development is unclear. Analyses of publicly available databases have revealed expression of transcripts at various levels of many cytokines and cytokine receptors such as IL-15, IL-15Rα, IL-13, and IL-23a in both human and mouse TECs. Ablation of either IL-15 or IL-15Rα in TECs selectively impairs type 1 innate like T cell, such as iNKT1 and γδT1 cell, development in the thymus, indicating that TECs not only serve as an important source of IL-15 but also trans-present IL-15 to ensure type 1 innate like T cell development. Because type 1 innate like T cells are proinflammatory, our data suggest the possibility that TEC may intrinsically control thymic inflammatory innate like T cells to influence thymic environment.
Authors
Tao, H; Li, L; Liao, N-S; Schluns, KS; Luckhart, S; Sleasman, JW; Zhong, X-P
MLA Citation
Tao, Huishan, et al. “Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development.Front Immunol, vol. 12, 2021, p. 623280. Pubmed, doi:10.3389/fimmu.2021.623280.
URI
https://scholars.duke.edu/individual/pub1476430
PMID
33732245
Source
pubmed
Published In
Frontiers in Immunology
Volume
12
Published Date
Start Page
623280
DOI
10.3389/fimmu.2021.623280

Research Areas:

Adaptive Immunity
Adjuvants, Immunologic
Administration, Oral
Anacardium
Anaphylaxis
Antigen Presentation
Antigens, Bacterial
Antigens, CD28
Antigens, CD3
Antigens, CD4
Antigens, CD45
Antigens, CD8
Antigens, Plant
Apoptosis
Arachis
Arachis hypogaea
Basophils
Bone Marrow
Bone Marrow Cells
CD28 Antigens
CD4 Antigens
CD4-Positive T-Lymphocytes
Cell Death
Cell Degranulation
Cell Differentiation
Cell Lineage
Cell Proliferation
Cell Transformation, Neoplastic
Child, Preschool
Chromatin Immunoprecipitation
DNA Nucleotidyltransferases
Dendritic Cells
Desensitization, Immunologic
Diacylglycerol Kinase
Diglycerides
Disease Models, Animal
Down-Regulation
Drosophila
Enhancer Elements, Genetic
Exons
Family
Female
Forkhead Transcription Factors
Gene Expression
Gene Expression Regulation
Gene Expression Regulation, Enzymologic
Gene Targeting
Genes, Immunoglobulin
Guanine Nucleotide Exchange Factors
Histocompatibility Antigens Class II
Homeostasis
Homozygote
Humans
Hypertrophy
I-kappa B Proteins
Immune Tolerance
Immunity, Innate
Immunoglobulin E
Immunoglobulin G
Immunosuppression
Immunotherapy
Inducible T-Cell Co-Stimulator Protein
Interferon Regulatory Factors
Interferon-gamma
Interleukin-12
Interleukin-17
Interleukin-2
Jurkat Cells
Killer Cells, Natural
Leukocyte Common Antigens
Loss of Heterozygosity
Lung Neoplasms
Lymphocyte Activation
Lymphocytic Choriomeningitis
Lymphopenia
Macrophages
Male
Mast Cells
Melanoma, Experimental
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Fluorescence
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinases
Models, Biological
Muscle Proteins
Muscle, Skeletal
Mutagenesis, Insertional
Natural Killer T-Cells
Neoplasm Proteins
Nut Hypersensitivity
Oligodeoxyribonucleotides
Organ Size
Peanut Hypersensitivity
Pepsin A
Phosphatidic Acids
Phosphatidylinositol 3-Kinases
Phospholipase D
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Protein Isoforms
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
RNA Interference
RNA, Small Interfering
Receptors, Antigen, T-Cell
Receptors, Antigen, T-Cell, alpha-beta
Receptors, Antigen, T-Cell, gamma-delta
Receptors, IgE
Recombinant Fusion Proteins
Self Tolerance
Signal Transduction
Skin Tests
Spleen
Survival Rate
T-Lymphocyte Subsets
T-Lymphocytes
T-Lymphocytes, Regulatory
TOR Serine-Threonine Kinases
Th1 Cells
Th2 Cells
Thymocytes
Toll-Like Receptor 4
Toll-Like Receptors
Toxoplasma
Toxoplasmosis
Trans-Activators
Transcription, Genetic
Transduction, Genetic
Transfection
Tuberous Sclerosis
Tumor Necrosis Factor-alpha
Tumor Suppressor Proteins
Uniparental Disomy
VDJ Recombinases
ras Proteins