Jianzhu Chen, Ph.D.
Department of Biology
Professor of Biology
Ph.D. 1990, Stanford University
Antigen Receptor Gene Assembly and Lymphoid Tumorigenesis:
The adaptive immune system is able to respond to a diverse array of pathogenic infections through specific receptors: T cell receptors (TCR) for T cells and immunoglobulin (Ig or antibody) for B cells. Antigen receptor genes are assembled from component V (variable), D (diversity), and J (joining) gene segments in a process called V(D)J recombination. Because V(D)J recombination involves generation and repair of DNA double strand breaks (DSBs), which can result in cell cycle arrest, genome instability, and tumorigenesis, the process is tightly controlled both before and after DNA cleavage. We have found that transcriptional enhancers and promoters regulate V(D)J recombination by regulating gene segment accessibility as well as stage- and site-specificity. Furthermore, we found that inactivation of transcription enhancers and promoters results in block of lymphocyte development that can cooperate with loss of p53 in lymphomagenesis. For example, introduction of the TCR beta enhancer mutation into p53-deficient mice dramatically accelerates the development of T cell lymphomas. We are investigating molecular mechanisms underlying the observed development of lymphomas in the mutant mice.
Cellular and Molecular Basis of Immunological Memory:
Immunological memory is the ability of lymphocytes to respond faster and more strongly to reencounter of the same antigen. It is a central feature of the adaptive immunity and is the basis of vaccination. However, little is known about the differentiation, maintenance, reactivation, and function of memory T cells. We have shown that as na´ve CD8 T cells undergo proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. We have also developed mouse models in which CD8 T cell response to influenza virus infection can be studied at any time and in any anatomical location. By comparing the two memory T cell differentiation pathways, we have identified that TCR engagement and cell proliferation are the two requirements for memory T cell development. We are currently investigating:
RNA interference of influenza virus infection:
- genes that are required for memory CD8 T cell development and maintenance
- how cell proliferation (DNA replication) leads to chromatin remodeling of specific genes whose expression characterizes the memory T cell phenotype
- CD8 T cell vaccines for prevention and/or treatment of virus infections in the respiratory tract.
Influenza A virus causes the most prevalent infection of the respiratory tract in humans. In a typical year, 10-20% of the population in the United States is afflicted by the virus, resulting in up to 40,000 deaths. In what was one of the most devastating human catastrophes in history, an estimated of 40-50 million people died worldwide during the 1918 influenza pandemic. The virulence of influenza A virus results from:
- its easy spread by aerosol
- its ability to escape from protective immunity by frequent changes in viral antigens (antigenic drift)
- the periodic emergence of new virulent strains by reassortment of gene segments between viruses from two different species (antigenic shift)
The threat of a new influenza pandemic persists as indicated by frequent outbreak of avian influenza viruses.
RNA interference (RNAi) is a process by which double-stranded RNA (dsRNA) directs sequence-specific degradation of messenger RNA (mRNA). Studies have shown that in mammalian cells RNAi can be triggered by synthetic 19-29-nucleotide short interfering RNA duplexes (siRNA). Because siRNAs are too short to induce an interferon response in mammalian cells, yet still able to confer transient interference of gene expression in a sequence specific manner, they represent a new class of molecules that may have significant medical applications. We have found that siRNAs specific for conserved regions of influenza viruses potently inhibit virus production in cultured cells, embryonated chicken eggs, and mice. We are interested in developing siRNA as prophylaxis and/or therapies for influenza virus infection in humans.
- Ge, Q., Filip, L., Bai, A., Nguyen, T., Eisen, H.N., Chen, J. Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc. Natl. Acad. Sci. USA. 101:8676:8681 (2004).
- Ryu, C.J., Haines, B.B., Lee, H.R., Kang, Y.H., Draganov, D.D. Whitehurst, C.E., Hong, H.J., Chen, J. The TCRb variable gene promoter is required for efficient Vb rearrangement but not allelic exclusion. Mol. Cell Biol. 2424:7015-7023. (2004).
- Ge, Q., Bai, A., Jones, B., Eisen, H.N., Chen, J. (2004) Competition for self-peptide-MHC complexes and cytokines between na´ve and memory CD8+ T cells expressing the same or different T cell receptors. Proc. Natl. Acad. Sci. USA. 101:304-3046.
- Cho, B., Varada, R., Ge, Q., Eisen, H.E., Chen, J. Homeostasis-stimulated proliferation drives na´ve T cells to differentiate directly into memory cells. J. Exp. Med. 192:549-556 (2000).
Last Updated: April 9, 2008