Dzhagalov, I, Dunkle, A, and He, Y-W. "The anti-apoptotic Bcl-2 family member Mcl-1 promotes T lymphocyte survival at multiple stages." J Immunol 181, no. 1 (July 1, 2008): 521-528.
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
Jia, W, Li, H, and He, Y-W. "Pattern recognition molecule mindin promotes intranasal clearance of influenza viruses." J Immunol 180, no. 9 (May 1, 2008): 6255-6261.
Zhang, N, Hopkins, K, and He, Y-W. "The long isoform of cellular FLIP is essential for T lymphocyte proliferation through an NF-kappaB-independent pathway." J Immunol 180, no. 8 (April 15, 2008): 5506-5511.
Miller, BC, Zhao, Z, Stephenson, LM, Cadwell, K, Pua, HH, Lee, HK, Mizushima, NN, Iwasaki, A, He, Y-W, Swat, W, and Virgin, HW. "The autophagy gene ATG5 plays an essential role in B lymphocyte development." Autophagy 4, no. 3 (April 2008): 309-314.
Wang, Q-Q, Li, H, Oliver, T, Glogauer, M, Guo, J, and He, Y-W. "Integrin beta 1 regulates phagosome maturation in macrophages through Rac expression." J Immunol 180, no. 4 (February 15, 2008): 2419-2428.
Pua, HH, and He, Y-W. "Maintaining T lymphocyte homeostasis: another duty of autophagy." Autophagy 3, no. 3 (May 2007): 266-267.
Dzhagalov, I, Chambon, P, and He, Y-W. "Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma." J Immunol 178, no. 4 (February 15, 2007): 2113-2121.
Dzhagalov, I, St John, A, and He, Y-W. "The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages." Blood 109, no. 4 (February 15, 2007): 1620-1626.
Pua, HH, Dzhagalov, I, Chuck, M, Mizushima, N, and He, Y-W. "A critical role for the autophagy gene Atg5 in T cell survival and proliferation." J Exp Med 204, no. 1 (January 22, 2007): 25-31.
Li, H, Oliver, T, Jia, W, and He, Y-W. "Efficient dendritic cell priming of T lymphocytes depends on the extracellular matrix protein mindin." EMBO J 25, no. 17 (September 6, 2006): 4097-4107.
Jia, W, Li, H, and He, Y-W. "The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment." Blood 106, no. 12 (December 1, 2005): 3854-3859.
Zhang, J, Guo, J, Dzhagalov, I, and He, Y-W. "An essential function for the calcium-promoted Ras inactivator in Fcgamma receptor-mediated phagocytosis." Nat Immunol 6, no. 9 (September 2005): 911-919.
Zhang, N, and He, Y-W. "An essential role for c-FLIP in the efficient development of mature T lymphocytes." J Exp Med 202, no. 3 (August 1, 2005): 395-404.
Zhang, N, and He, Y-W. "The antiapoptotic protein Bcl-xL is dispensable for the development of effector and memory T lymphocytes." J Immunol 174, no. 11 (June 1, 2005): 6967-6973.
Dzhagalov, I, Giguère, V, and He, Y-W. "Lymphocyte development and function in the absence of retinoic acid-related orphan receptor alpha." J Immunol 173, no. 5 (September 1, 2004): 2952-2959.