Our research interests are to understand cellular and molecular mechanisms underlying the development and function of the immune system. We specifically study i) control of antigen receptor gene assembly and dysregulation of the process in lymphoid tumorigenesis, and ii) cellular and molecular basis of immunological memory, focusing on CD8 T cell responses to virus infection in the lung and prostate cancer. We are developing novel prophylaxis and therapies against virus infection in the lung.
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.
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 naïve 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:
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:
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 Bio. 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 naïve 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 naïve T cells to differentiate directly into memory cells. Exp. Med. 192:549-556 (2000)
room E17-131
phone (617) 258-6173
email jchen@mit.edu
phone (617) 324-5100
fax (617) 258-6172
Ryan Hayman
phone (617) 253-0796
email rhayman@mit.edu
