Zhao, BB, Zheng, SJ, Gong, LL, Wang, Y, Chen, CF, Jin, WJ, Zhang, D, Yuan, XH, Guo, J, Duan, ZP, and He, YW. "T Lymphocytes from Chronic HCV-Infected Patients Are Primed for Activation-Induced Apoptosis and Express Unique Pro-Apoptotic Gene Signature." PLoS ONE 8, no. 10 (October 10, 2013).
You-Wen He, MD, PhD
We study T cell biology in health and disease. Our current study is divided into two parts. Part I is to investigate T lymphocyte-mediated anti-caner immunity. We have found that host complement inhibits the cytokine IL-10 production in CD8+ tumor infiltrating lymphocytes through complement receptors C3aR and C5aR. Complement-deficient animals are resistant to tumor development in a T cell- and IL-10-dependent manner. CD8+ tumor infiltrating T cells express IL-10 when complement signaling is disabled. We found that tumor infiltrating lymphocytes from human cancers expanded with IL-2 plus IL-10 are potent tumor killers. Complement-mediated inhibition on antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ tumor infiltrating lymphocytes represent a novel class of immune checkpoints that needs to be targeted for tumor immunotherapy. Our current effort is to enhance cancer immunotherapy through several strategies. First, we investigate a combined blockade of complement signaling and anti-PD-1 to enhance the antitumor efficacy; second, we are studying the antitumor efficacy of a targeted delivery of IL-10 to antitumor CD8+ T cells by using anti-PD1-IL-10 or anti-CTLA-4-IL-10 fusion proteins; third, we are studying the tumor killing efficacy of addition of IL-10 in the expansion protocol of tumor infiltrating lymphocytes for adaptive cellular therapy.
Part II is to investigate the intracellular process termed autophagy in T lymphocyte function. Autophagy is a highly conserved self-digestion pathway that plays essential roles in maintaining the homeostasis of organelles, degrading long-lived proteins and recycling amino acids under starvation conditions. We have found that autophagy related molecules are expressed in T lymphocytes and autophagy occurs inside T lymphocytes. We have generated autophagy-deficient T lymphocytes in multiple genetic models and investigated the roles of autophagy in T lymphocytes. We found that autophagy plays a critical role in T lymphocyte function. Our current effort is to elucidate the molecular pathways by which TCR signal induces autophagy and the impact of autophagy on intracellular organelle homeostasis in dividing T cells.
Education and Training
- Senior Fellow, Immunology, University of Washington, 1996 - 2000
- Ph.D., University of Miami, 1996
- M.D., Fourth Military Medical University (China), 1986
Selected Grants and Awards
- Medical Scientist Training Program
- Organization and Function of Cellular Structure
- Basic Immunology Training Program
- Quinolizidines as Novel HIV-1 Entry Inhibitors
- Regulation of T cell exhaustion by microRNA-720
- Training Program in Inflammatory and Immunological Diseases
- Validation of a microRNA signature for the prediction, diagnosis and prognosis of acute graft-versus-host disease
- Plasma microRNAs as non-invasive biomarker for acute graft-versus-host diseases
- Autophagy in T lymphocyte function
- BcI-2 family in T lymphocyte homeostasis
- Regulation of thymocyte maturation and mature T lymphocyte homeostasis by c-FLIP
- The effects of Nlrp12 and IL-1b in inflammatory disorders
- A novel pathway regulating cytokine production and asthma development
- Function of thymic epithelial cells in T lymphocyte maturation
- Extracellular Matrix Protein in Innate Immunity
- Pattern Recognition Molecule Mindin As Adjuvant
- Orphan Nuclear Receptor in Thymocyte Differentiation
He, MX, Wan, Y, and He, YW. "Role of the Autophagy Gene Atg5 in T Lymphocyte Survival and Proliferation." (October 1, 2013): 239-244. (Chapter)
He, M-X, and He, Y-W. "A role for c-FLIP(L) in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes." Cell Death Differ 20, no. 2 (February 2013): 188-197.
Dunkle, A, Dzhagalov, I, Gordy, C, and He, Y-W. "Transfer of CD8+ T cell memory using Bcl-2 as a marker." J Immunol 190, no. 3 (February 1, 2013): 940-947.
Jia, W, He, M-X, McLeod, IX, and He, Y-W. "Autophagy, a novel pathway to regulate calcium mobilization in T lymphocytes." Frontiers in Immunology 4, no. JUL (2013).
He, M-X, and He, Y-W. "CFLAR/c-FLIPL: A star in the autophagy, apoptosis and necroptosis alliance." Autophagy 9, no. 5 (2013): 791-793.
Zhang, Z-N, Xu, J-J, Fu, Y-J, Liu, J, Jiang, Y-J, Cui, H-L, Zhao, B, Sun, H, He, Y-W, Li, Q-J, and Shang, H. "Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression." Clinical Chemistry 59, no. 8 (2013): 1175-1186.
Piao, X, Komazawa-Sakon, S, Nishina, T, Koike, M, Piao, J-H, Ehlken, H, Kurihara, H, Hara, M, Van Rooijen, N, Schütz, G, Ohmuraya, M, Uchiyama, Y, Yagita, H, Okumura, K, He, Y-W, and Nakano, H. "c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. (Published online)" Sci Signal 5, no. 255 (December 18, 2012): ra93-.
McLeod, IX, and He, Y-W. "Editorial: TRPV1: how thymocytes sense stress and respond with autophagy." J Leukoc Biol 92, no. 3 (September 2012): 409-411.
McLeod, IX, Jia, W, and He, Y-W. "The contribution of autophagy to lymphocyte survival and homeostasis." Immunol Rev 249, no. 1 (September 2012): 195-204. (Review)
Wang, Y, Wang, XD, Lapi, E, Sullivan, A, Jia, W, He, Y-W, Ratnayaka, I, Zhong, S, Goldin, RD, Goemans, CG, Tolkovsky, AM, and Lu, X. "Autophagic activity dictates the cellular response to oncogenic RAS." Proc Natl Acad Sci U S A 109, no. 33 (August 14, 2012): 13325-13330.
Paul, S, Kashyap, AK, Jia, W, He, Y-W, and Schaefer, BC. "Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-κB." Immunity 36, no. 6 (June 29, 2012): 947-958.
Jin, W-J, Chen, C-F, Liao, H-Y, Gong, L-L, Yuan, X-H, Zhao, B-B, Zhang, D, Feng, X, Liu, J-J, Wang, Y, Chen, G-F, Yan, H-P, and He, Y-W. "Downregulation of the AU-rich RNA-binding protein ZFP36 in chronic HBV patients: implications for anti-inflammatory therapy." PLoS One 7, no. 3 (2012): e33356-.
He, M-X, McLeod, IX, Jia, W, and He, Y-W. "Macroautophagy in T lymphocyte development and function. (Published online)" Front Immunol 3 (2012): 22-.
Gordy, C, and He, Y-W. "The crosstalk between autophagy and apoptosis: Where does this lead?." Protein and Cell 3, no. 1 (2012): 17-27.