Breadcrumb

Senior Investigator

Vanja Lazarevic, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Experimental Immunology Branch

RESEARCH SUMMARY

Dr. Lazarevic’s laboratory is interested in how transcription factors regulate differentiation and effector function of CD4+ T helper (Th) cells in the context of autoimmune disorders with emphasis on experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Her research is focused on understanding the molecular basis for functional plasticity of CD4+ Th cells and identifying CD4+ T cell-specific, pathogenicity-associated genes required for initiation and propagation of inflammation. Transcription factor T-bet has been linked to the development of several autoimmune diseases. Dr. Lazarevic’s laboratory is validating the importance of T-bet target genes in driving the pathogenesis of multiple sclerosis with the aim of developing new lines of therapeutic agents.

Areas of Expertise

1) CD4 T helper cells 2) transcription factors 3) autoimmunity

Research

Our laboratory studies the molecular events that lead to the breakdown of immunological tolerance to self-antigens. These processes are clinically manifested in the development of autoimmune diseases, such as multiple sclerosis or rheumatoid arthritis.

The function of the immune system is to defend the host against viral, bacterial, fungal and parasitic challenges. This protection is mediated through the cells of both innate and adaptive immunity. The cells of adaptive immunity (T cells and B cells) possess antigen-specific receptors of extraordinary diversity in order to protect the body from pathogens. A by-product of this system is the generation of T and B cell subsets which possess receptors that recognize host antigens ("self-antigens"). Exquisite mechanisms have evolved to suppress these autoreactive cells and prevent them from activation by self-antigens. When self-tolerance fails due to environmental or genetic factors, susceptible individuals develop autoimmune diseases which affect either specific organs or the entire body (systemic autoimmunity).

The focus of our laboratory is to understand at a fundamental level the gene products (with a special emphasis on transcription factors) responsible for the breakdown of self-tolerance.

To elucidate the nature of immunological dysregulation that leads to the development of autoimmunity, our lab is focused on the pathogenesis of multiple sclerosis. This is a complex disease in which cells of the immune system attack the protective myelin sheath that wraps around neurons in the brain, spinal cord and optic nerves. Relentless and unchecked immune system activation in the central nervous system (CNS) leads to irreversible neuronal damage and, ultimately, paralysis of affected individuals.

Most of our understanding of the pathogenesis of multiple sclerosis comes from investigations using an experimental autoimmune encephalomyelitis (EAE) animal model. In this model, both CD4+ Th1 and Th17 cells contribute to the pathogenesis of the disease. Our overall goal is to understand how transcription factors and their downstream targets affect CD4+ Th cell differentiation and effector function in the context of autoimmune diseases using this EAE animal model.

Image
Localization of T-bet-dependent NKp46+ ILCs during EAE
2D2 CD4+ TH17 cells were adoptively transferred into NKp46+ reporter mice (NKp46-Cre+ Rosa26-loxP-STOP-loxP-YFP). Spinal cord meninges were isolated from NKp46+ reporter mice before the onset of symptoms (score 0) and during the peak of disease (score 3) and stained with DAPI and anti-MHCII (I-A/I-E). Inset images show clusters of NKp46+ (green) and 2D2 CD4+ T cells (white), without (left) and with (right) MHCII (I-A/I-E) staining. Scale bars, 500 mm for main images or 40 mm for insets. 
NIH Scientific Focus Areas
Immunology
Neuroscience

Publications

Selected Key Publications

Transcriptional regulation of CD4+ TH cells that mediate tissue inflammation

TT Loo, Y Gao, V Lazarevic
Journal of Leukocyte Biology. 104 (6): 1069-1085, 2018. [ Journal Article ]

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation

Brandon Kwong, Rejane Rua, Yuanyuan Gao, John Flickinger Jr, Yan Wang, Michael J Kruhlak, Jinfang Zhu, Eric Vivier, Dorian B McGavern, Vanja Lazarevic
Nature Immunology. 18 (10): 1117-1127, 2017. [ Journal Article ]

The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells

Yan Wang, Jernej Godec, Khadija Ben-Aissa, Kairong Cui, Keji Zhao, Alexandra B Pucsek, Yun Kyung Lee, Casey T Weaver, Ryoji Yagi, Vanja Lazarevic
Immunity. 40 (3): 355-366, 2014. [ Journal Article ]

Transcriptional regulation of adaptive and innate lymphoid lineage specification

Camille A. Spinner, Vanja Lazarevic
Immunological Reviews. 300(1): 65-81, 2021.
Full-Text Article
[ Journal Article ]

T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Vanja Lazarevic, Xi Chen, Jae-Hyuck Shim, Eun-Sook Hwang, Eunjung Jang, Alexandra N Bolm, Mohamed Oukka, Vijay K Kuchroo, Laurie H Glimcher
Nature Immunology. 12 (1): 96-104., 2011. [ Journal Article ]

Covers

Nature Immunology Cover October 2017

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation.

Published Date

The process by which self-reactive CD4+ T cells infiltrate the central nervous system (CNS) and trigger neuroinflammation is not fully understood. Lazarevic and colleagues show that NKp46+innate lymphoid cells dependent on the transcription factor T-bet are critical mediators in facilitating the entry of autoreactive CD4+ cells of the TH17 subset of helper T cells into the CNS, which leads to autoimmunity. Artwork by Lewis Long.

Citation

Original article: Nature Immunology 2017 Oct;18(10):1117-1127. doi:10.1038/ni.3816. 

News and Views: Nature Immunology 2017 Oct;18(10):1063-1064. doi:10.1038/ni.3839