Professor of Biology
KI Research Areas of Focus:
Professor of Biology
KI Research Areas of Focus:
"We seek to understand the cellular and molecular mechanisms underlying the development and function of the immune system. Our goal is that the knowledge we gain will lead to more effective immunotherapies for cancer and other diseases. Our laboratory focuses on a particular class of immune cells – CD8 T-cells –which play an important role in the ability of the immune system to respond more strongly to threats that have been encountered before. We investigate CD8 T –cell responses to the influenza virus and to prostate cancer. Our laboratory is also actively engaged in developing improved mouse models of the human immune system, so that our experimental systems most closely reflect the clinical reality."
Dr. Chen received a B.S. degree from Wuhan University in China and a Ph.D. in Genetics from Stanford University in 1990. He was a post-doctorial fellow and then an instructor at Harvard Medical School before he joined the MIT faculty in the Department of Biology.
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 locations. 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 in 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 persisting tolerized 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 establishment of infection models of human pathogens, such as HIV, the current system is far from optimal. First, only a small cohort of humanized mice (~10) can be constructed with HSCs from a single cord blood. This number is too small for any significant study. Second, reconstitution of myeloid cells, which mediate innate immune responses, is generally poor in the humanized mice. Third, HSCs have not been easily amenable to genetic modification, which is critical for studying gene function in immune responses to specific pathogens. We have made breakthroughs in overcoming the three limitations. First, we have developed two methods to expand HSCs in vitro so that large number of humanized mice can be made using HSCs from the same source. Second, we have devised a simple method to enhance reconstitution of specific subset of myeloid cells in reconstituted mice by expressing appropriate human cytokines. Third, we have developed methods to genetically modify HSCs prior to their transfer into NSG mice. As a proof-of-concept, we have introduced proto-oncogenes into HSCs and developed a human B cell leukemia/lymphoma model in mice. Development of a better humanized mouse model will provide an important tool for studying human immune responses and diseases in a small animal model.
Kaur M, Drake AC, Hu G, Rudnick S, Chen Q, Phennicie R, Attar R, Nemeth J, Gaudet F, Chen J. Induction and Therapeutic Targeting of Human NPM1c+ Myeloid Leukemia in the Presence of Autologous Immune System in Mice. J Immunol. 2019 Mar 15;202(6):1885-1894. doi: 10.4049/jimmunol.1800366. Epub 2019 Feb 1. PMID: 30710044
Drake A, Kaur M, Iliopoulou BP, Phennicie R, Hanson A, Chen J. Interleukins 7 and 15 Maintain Human T Cell Proliferative Capacity through STAT5 Signaling. PLoS One. 2016 Nov 17;11(11):e0166280. doi: 10.1371/journal.pone.0166280. eCollection 2016. PMID: 27855183
Roghanian A, Fraser C, Kleyman M, Chen J. B Cells Promote Pancreatic Tumorigenesis. Cancer Discov. 2016 Mar;6(3):230-2. doi: 10.1158/2159-8290.CD-16-0100. PMID: 26951836
Chen Q, Ye W, Jian Tan W, Mei Yong KS, Liu M, Qi Tan S, Loh E, Te Chang K, Chye Tan T, Preiser PR, Chen J. Delineation of Natural Killer Cell Differentiation from Myeloid Progenitors in Human.Sci Rep. 2015 Oct 12;5:15118. doi: 10.1038/srep15118. PMID: 26456148
Li Y, Shen C, Zhu B, Shi F, Eisen HN, Chen J. Persistent Antigen and Prolonged AKT-mTORC1 Activation Underlie Memory CD8 T Cell Impairment in the Absence of CD4 T Cells. J Immunol. 2015 Aug 15;195(4):1591-8. doi: 10.4049/jimmunol.1500451. Epub 2015 Jul 10. PMID: 26163589
Bak SP, Barnkob MS, Wittrup KD, Chen J. CD8+ T-cell responses rapidly select for antigen-negative tumor cells in the prostate. Cancer Immunol Res. 2013 Dec;1(6):393-401. doi: 10.1158/2326-6066.CIR-13-0109. Epub 2013 Sep 20. PMID: 24778132
Hu G, Chen J. A genome-wide regulatory network identifies key transcription factors for memory CD8⁺ T-cell development. Nat Commun. 2013;4:2830. doi: 10.1038/ncomms3830. PMID: 24335726
Chen Q, Khoury M, Chen J. Expression of human cytokine genes dramatically improves reconstitution of specific human blood lineage cells in humanized mice. Proc Natl. Acad. Sci. USA,2009;106:21783-21788.
Bai A, Higham E, Wittrup D, Eisen HN, Chen J. Rapid tolerization of tumor-infiltrating effector T cells in the prostate of TRAMP mice. Proc. Nat. Acad. Sci. USA, 2008;105:13003-8.
Shen C-H, Ge Q, Talay O, Eisen HN, Garcia-Sastre A, Chen J. Loss of interleukin (IL)-7 and IL-15 receptors is associated with disappearance of memory CD8 T cells in respiratory track. J. Immunol. 2008;180:171-8 (2008).
Cho B, Varada R, Ge Q, Eisen HE, Chen J. Homeostasis-stimulated proliferation drives naïve T cells to differentiate directly into memory cells. J. Exp. Med. 2000;192:549-556.