Dr. Xiang’s Lab focuses on (i) studying the molecular mechanism regulating CD8+ T cell fate and memory formation, (ii) assessing the critical role of CD4+ T cell help in CD8+ T cell immunity, and (iii) developing novel HER2- and Gag-specific exosome-targeted T cell vaccines for HER2+ breast cancer and HIV-1 patients.
1. Molecular pathways for CD8+ T cell fate and memory: Understanding the molecular pathway controlling CD8+ T cell fate and memory is critically important in vaccine development and immunotherapy. We recently discover that mannose-6 phosphate receptor (M6PR) specific for lytic granule Granzyme-B (GB) plays a critical role controlling T cell fate. M6PRhigh CD8+ T cells die of GB-mediated lethal hit, while M6PRlow ones survive in the contraction. We further elucidate that pro-inflammation cytokine IL-2 induces M6PRhigh CD8+ T cells while pro-survival cytokine IL-7 stimulates M6PRlow ones differentiating into long-term memory T cells. The IL-2-stimutaed strong activation of mTORC1 up-regulates motor protein KIF13A leading delivery of more M6PR onto cell surface of IL-2-activated CD8+ T cells susceptible for GB-mediated killing, and vis-à-vis for the IL-7-stimulated weak mTORC1 activation. We are currently studying the molecular pathway regulating the memory T cell differentiation of IL-7-induced M6PRlow CD8+ T cells.
2. A new concept "Th-APC": A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T cells in priming of CD8+ cytotoxic T lymphocyte (CTL)responses. We found that CD4+ Th cells can acquire synapse-composed pMHC I and II and CSM from APCs via trogocytosis, and become Th‐APCs capable of stimulating CD8+ T cell response and memory.Therefore, this new conceptual advance may have great impacts in antitumor and autoimmune responses. We are currently studying molecular mechanisms of CD4+ T cell help in CD8+ T cell immunity and memory.
3. Exosome-targeted T cell-based vaccines: Based upon the new concept of “Th-APC”, we developed CD4+ T cell‐based vaccines using polyclonal CD4+ T cells with uptake of Ag‐specific dendritic cell (DC)-released exosomes (EXO), and demonstrate that the novel vaccine is capable of directly stimulating potent CD8+ CTL effector and memory responses, counteracting CD4+ Tr‐mediated immune suppression, and converting CTL exhaustion via its CD40L signaling activation of mTORC1 pathway in chronic infection. We are currently developing HER-2/neu-specific and HIV-1 Gag-specific exosome-targeted T cell vaccines for treatment of HER-2/neu-positive breast cancer and HIV-1 patients.
Selected Recent Publications
1. Xie Y, Wang L, Frewald A, Qureshi M, Chen Y and Xiang J. Novel T cell-based vaccine capable of stimulating long-term functional CTL memory against B16 melanoma via CD40L signaling. Cell Mol Immunol. 10: 72-77, 2013.
2. Umeshappa C S, Nanjundappa R, Freywald A and Xiang J. Differential requirements of CD4+ T cell signals for effector cytotoxic T lymphocyte (CTL) priming and functional memory CTL development at higher CD8+ T cell precursor frequency. Immunol 138: 298-306, 2013.
3. Wang L, Xie Y, Ahmed K, Ahmed S, Sami A, Chibbar R, Xu Q, Kane S, Hao S, Mulligan S and Xiang J. Exosomal pMHC-I complexes target T cell-based vaccine to directly stimulate CTL responses leading to antitumor immunity in transgenic FVBneuN and HLA-A2/HER2 mice and eradicating trastuzumab-resistant tumor in athymic nude mice. Breast Cancer Res Treat 140: 273-284, 2013.
4. Wang R, Freywald A, Chen Y, Xu J and Xiang J. Transgene 41BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via priming CD44+CD62LhighIL-7R+ CTLs with up- and down-regulation of anti- and pro-apoptosis genes. Cell Mol Immunol, 12: 456-465, 2015.
5. Ahmed K, Wang L, Griebel P, Mousseau D and Xiang J. Differential expression of mannose-6-phosphate receptor regulates T cell contraction. J Leuk Biol, 98: 313-318, 2015.
6. Zhao T, Tan X, Umeshappa C, Ma H, Gao H, Deng Y, Freywald A and Xiang J. Simulated microgravity promotes cell apoptosis through suppression of Uev1A/TICAM/TRAF/NF-kB-regulated anti-apoptosis and p53/PCNA- and ATM/ATR-Chk1/2-controlled DNA-damage response pathways. J Cell Biochem. 117: 2138-2148, 2016.
7. Xu A, Ye Z, Wu J, Leary S, Li R and Xiang J. Irradiation-induced lymphopenia promotes T cell survival via IL-15 signaling STAT5/Bcl2 pathway and enhances T cell memory via IL-15 activation of FOXO/Eomes memory and ULK1/Atg7 autophage pathways. Cell Bioscience. 6: 30, 2016.
8. Wang R, Xu A, Zhang X, Wu J, Freywald A, Xu J and Xiang J. Novel exosome-targeted T cell-based vaccine counteracts T cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway. Cell Mol Immunol, 14: 529-545, 2017.
9. Mu C, Zhang X, Wang L, Xu A, Ahmed A, Pang X, Chibbar R, Freywald A, Huang J, Zhu Y and Xiang J. Enhanced suppression of polyclonal CD8+25+ regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes. J Leuk Biol. 101: 1221-1231, 2017.
10. Khawaja Ashfaque Ahmed and Xiang J. mTORC1 regulates mannose-6-phosphate receptor and T cell vulnerability to regulatory T cells by controlling kinesin KIF13A. Cell Discovery, 3: 17011, 2017.