Schattenberg, JM, Zimmermann, T, Wörns, M, Sprinzl, MF, Kreft, A, Kohl, T, Nagel, M, Siebler, J, Schulze Bergkamen, H, He, Y-W, Galle, PR, and Schuchmann, M. "Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo." J Hepatol 55, no. 6 (December 2011): 1272-1280.
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
McLeod, IX, Zhou, X, Li, Q-J, Wang, F, and He, Y-W. "The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression." J Immunol 187, no. 10 (November 15, 2011): 5051-5061.
Dunkle, A, Dzhagalov, I, and He, Y-W. "Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes. (Published online)" Cell Death Dis 2 (October 6, 2011): e214-.
Jia, W, and He, Y-W. "Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy." J Immunol 186, no. 9 (May 1, 2011): 5313-5322.
Altman, BJ, Jacobs, SR, Mason, EF, Michalek, RD, MacIntyre, AN, Coloff, JL, Ilkayeva, O, Jia, W, He, Y-W, and Rathmell, JC. "Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis." Oncogene 30, no. 16 (April 21, 2011): 1855-1867.
Dunkle, A, and He, Y-W. "Apoptosis and autophagy in the regulation of T lymphocyte function." Immunol Res 49, no. 1-3 (April 2011): 70-86. (Review)
Jia, W, Pua, HH, Li, Q-J, and He, Y-W. "Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes." J Immunol 186, no. 3 (February 1, 2011): 1564-1574.
Gordy, C, Pua, H, Sempowski, GD, and He, Y-W. "Regulation of steady-state neutrophil homeostasis by macrophages." Blood 117, no. 2 (January 13, 2011): 618-629.
Dunkle, A, Dzhagalov, I, and He, Y-W. "Mcl-1 promotes survival of thymocytes by inhibition of Bak in a pathway separate from Bcl-2." Cell Death Differ 17, no. 6 (June 2010): 994-1002.
Pua, HH, and He, Y-W. "Mitophagy in the little lymphocytes: an essential role for autophagy in mitochondrial clearance in T lymphocytes." Autophagy 5, no. 5 (July 2009): 745-746.
Pua, HH, Guo, J, Komatsu, M, and He, Y-W. "Autophagy is essential for mitochondrial clearance in mature T lymphocytes." J Immunol 182, no. 7 (April 1, 2009): 4046-4055.
Li, Y, Cao, C, Jia, W, Yu, L, Mo, M, Wang, Q, Huang, Y, Lim, J-M, Ishihara, M, Wells, L, Azadi, P, Robinson, H, He, Y-W, Zhang, L, and Mariuzza, RA. "Structure of the F-spondin domain of mindin, an integrin ligand and pattern recognition molecule." EMBO J 28, no. 3 (February 4, 2009): 286-297.
Gordy, C, Dzhagalov, I, and He, Y-W. "Regulation of CD8(+) T cell functions by RARgamma." Semin Immunol 21, no. 1 (February 2009): 2-7. (Review)
Pua, HH, and He, Y-W. "Autophagy and lymphocyte homeostasis." Curr Top Microbiol Immunol 335 (2009): 85-105. (Review)
Zhang, N, Hopkins, K, and He, Y-W. "c-FLIP protects mature T lymphocytes from TCR-mediated killing." J Immunol 181, no. 8 (October 15, 2008): 5368-5373.