Our research interests are to understand cellular and molecular mechanisms underlying the development and function of the immune system. We specifically study: (i) Cellular and molecular basis of immunological memory (ii) CD8 T cell responses to prostate cancer (iii) Development of a robust humanized mouse model
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. Using this model, we have identified factors that promote the development and maintenance of central versus effector memory T cells. In the long-term, we are interested in elucidating the molecular pathways of memory CD8 T cell development and identifying conditions for the optimal induction and maintenance of CD8 memory T cells for vaccination.
CD8 T cells are critical for the clearance of virus infection as well as tumor cells. Harnessing the power of CD8 immunity to kill tumor cells has been a long-term goal of cancer immunotherapy. We have developed a mouse model in which CD8 T cell response and tolerance to a spontaneous prostate cancer can be monitored in detail. We have shown that tumor-specific CD8 T cells can be activated in tumor-bearing mice by virus infection. Although the resulting effector CD8 T cells infiltrate prostate tumor and remain functional in the tumor tissue for several days, eventually the T cells are inactivated or tolerized by the persistent expression of tumor antigen and the tumor environment. Interestingly, a population of tumor-specific CD8 T cell persists in the tumor tissue, analogous to the tumor-infiltrating lymphocytes in human. We are investigating the basis for the persistence of tumor-specific CD8 T cells in the tumor tissue and developing approaches to delay the tolerance induction and reactivate the tumor-specific CD8 T cells. Findings from these studies may help develop more effective cancer immunotherapy.
There has been a great need to study human immune responses to pathogenic infections in a systematic and controlled manner. For this reason, tremendous efforts have been devoted to reconstitute severe combined immunodeficient (scid) mice, which lack their own T and B lymphocytes, with human immune cells. However, early approaches were unsuccessful because of poor implantation efficiency, or rapid disappearance of human T and B cells from recipient mice, or rapid development of hematopoietic malignancies in recipient mice. A breakthrough was reported recently by using scid mice that were also deficient in the common gamma chain. Although the existing humanized mouse model begins to allow investigations of human pathogen infections in a small animal model, the current system is not ideal. For example, the immune response in the humanize mice is poor. In addition, it is difficult to genetically modify hematopoietic stem cells prior to their transfer into mice. Obviously, this is necessary if one would like to test specific gene function in the immune responses to the pathogen of interest. We have established the humanized mouse model and made significant progress in expanding human hematopoietic stem cells in vitro and genetically modifying them with lentivirus. We aim to develop a robust humanized mouse model for studying human immune responses to infections and evaluating therapeutics for human diseases in the hematopoietic system.
Bai, A., Higham, E., Eisen, H.N., Wittrup, K.D., Chen, J. Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13003-8.
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)
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
