He, Y-W, Li, H, Zhang, J, Hsu, C-L, Lin, E, Zhang, N, Guo, J, Forbush, KA, and Bevan, MJ. "The extracellular matrix protein mindin is a pattern-recognition molecule for microbial pathogens." Nat Immunol 5, no. 1 (January 2004): 88-97.
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
Zhang, N, Guo, J, and He, Y-W. "Lymphocyte accumulation in the spleen of retinoic acid receptor-related orphan receptor gamma-deficient mice." J Immunol 171, no. 4 (August 15, 2003): 1667-1675.
He, Y-W. "Orphan nuclear receptors in T lymphocyte development." J Leukoc Biol 72, no. 3 (September 2002): 440-446. (Review)
Guo, J, Hawwari, A, Li, H, Sun, Z, Mahanta, SK, Littman, DR, Krangel, MS, and He, Y-W. "Regulation of the TCRalpha repertoire by the survival window of CD4(+)CD8(+) thymocytes." Nat Immunol 3, no. 5 (May 2002): 469-476.
He, YW, Beers, C, Deftos, ML, Ojala, EW, Forbush, KA, and Bevan, MJ. "Down-regulation of the orphan nuclear receptor ROR gamma t is essential for T lymphocyte maturation." J Immunol 164, no. 11 (June 1, 2000): 5668-5674.
He, YW. "The role of orphan nuclear receptor in thymocyte differentiation and lymphoid organ development." Immunol Res 22, no. 2-3 (2000): 71-82. (Review)
He, YW, and Bevan, MJ. "High level expression of CD43 inhibits T cell receptor/CD3-mediated apoptosis." J Exp Med 190, no. 12 (December 20, 1999): 1903-1908.
Malek, TR, Porter, BO, and He, YW. "Multiple gamma c-dependent cytokines regulate T-cell development." Immunol Today 20, no. 2 (February 1999): 71-76. (Review)
Deftos, ML, He, YW, Ojala, EW, and Bevan, MJ. "Correlating notch signaling with thymocyte maturation." Immunity 9, no. 6 (December 1998): 777-786.
He, YW, Deftos, ML, Ojala, EW, and Bevan, MJ. "RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells." Immunity 9, no. 6 (December 1998): 797-806.
Malek, TR, Levy, RB, Adkins, B, and He, YW. "Monoclonal antibodies to the common gamma-chain as cytokine receptor antagonists in vivo: effect on intrathymic and intestinal intraepithelial T lymphocyte development." J Leukoc Biol 63, no. 6 (June 1998): 643-649. (Review)
He, YW, and Malek, TR. "The structure and function of gamma c-dependent cytokines and receptors: regulation of T lymphocyte development and homeostasis." Crit Rev Immunol 18, no. 6 (1998): 503-524. (Review)
He, YW, Nakajima, H, Leonard, WJ, Adkins, B, and Malek, TR. "The common gamma-chain of cytokine receptors regulates intrathymic T cell development at multiple stages." J Immunol 158, no. 6 (March 15, 1997): 2592-2599.
He, YW, and Malek, TR. "Interleukin-7 receptor alpha is essential for the development of gamma delta + T cells, but not natural killer cells." J Exp Med 184, no. 1 (July 1, 1996): 289-293.
He, YW, and Malek, TR. "The IL-2 receptor gamma c chain does not function as a subunit shared by the IL-4 and IL-13 receptors. Implication for the structure of the IL-4 receptor." J Immunol 155, no. 1 (July 1, 1995): 9-12.