The immune system strikes a kaleidoscope way to eliminate different types of infections and cancerous cells. While immune deficiency leads to susceptibility to infections and cancers, the trade-off of “strong” immune responses is the risk of autoimmune diseases and inflammation. Maintenance of a competent but balanced immune system is the cornerstone of health. The sophisticated immune defence mechanisms are essentially orchestrated by T cells. Not only can T cells directly kill infected and cancerous cells, but they also, through multiple subsets, fundamentally control the activation and function of other immune cell types. Therefore, targeted regulation of T cells subsets can efficiently modulate immune responses to treat many human diseases.
In the lab of T-cell Immune Mechanism, Monitoring and Modulation (TIM3), Dr Di Yu and his team are investigating the molecular mechanisms by which T cells control the competence and balance of the immune system, with the aim to design new strategies to modulate the immune system to treat autoimmune disease, infection and cancer.
Three major approaches are used in our research. First, we use gene-targeted mice to investigate basic molecular mechanisms of the adaptive immunity, particularly for T cells and cytokines. Second, we phenotype immune cells using methods such as multi-colour flow cytometry to monitor the immune system of patients to understand the dysregulated immune responses associated with diseases and the immunological changes responding to therapies. Third, based on biochemical and structural knowledge of cytokines, we design and optimize cytokine-based immunotherapies to modulate the immune system to treat human diseases.
Fig: Lymph node section from HIV-infected patients. Photo shows anti-virus cytotoxic T cells (green) is adjacent to the HIV-infected cells (red) inside a B cell follicle (blue).
Leong YA, Chen Y, Ong HS, Wu D, Man K, Deleage C, Minnich M, Meckiff BJ, Wei Y, Hou Z, Zotos D, Fenix KA, Atnerkar A, Preston S, Chipman JG, Beilman GJ, Allison CC, Sun L, Wang P, Xu J, Toe JG, Lu HK, Tao Y, Palendira U, Dent AL, Landay AL, Pellegrini M, Comerford I, McColl SR, Schacker TW, Long HM, Estes JD, Busslinger M, Belz GT, Lewin SR, Kallies A*, Yu D*. (2016) CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nature Immunology 17(10):1187-96
He J#, Zhang X#, Wei Y#, Sun X, Chen Y, Deng J, Jin Y, Gan Y, Hu X, Jia R, Xu C, Hou Z, Leong YA, Zhu L, Feng J, An Y, Jia Y, Li C, Liu X, Ye H, Ren L, Li R, Yao H, Li Y, Chen S, Zhang X, Su Y, Guo J, Shen N, Morand EF, Yu D* and Li Z* (2016). Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nature Medicine 22(9): 991-3
Vinuesa CG*, Linterman MA*, Yu D*, MacLennan ICM (2016) Follicular Helper T Cells. Annual Review of Immunology 34:335-68
Yu D, Chen Y, Leong YA (2014) Navigating double negatives: new pathways for regulating T(FH) differentiation. Nature Immunology 15(7): 597-9
Yu D (2014) MicroRNAs in Tfh cells: mircomanaging inflammaging. Immunity 41(4): 509-511
He J#, Tsai LM#, Leong YA, Hu X, Ma CS, Chevalier N, Sun X, Vandenberg K, Rockman S, Ding Y, Zhu L, Wei W, Wang C, Karnowski A, Belz GT, Ghali JR, Cook MC, Riminton DS, Veillette A, Schwartzberg PL, Mackay F, Brink R, Tangye SG, Vinuesa CG, Mackay CR, Li Z*, Yu D*. (2013) Circulating precursor CCR7loPD-1hi CXCR5+ CD4+ T cells indicate follicular helper T cell activity and promote antibody responses upon antigen re-exposure. Immunity 39(4),770-781
Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma C, Li QJ, Parish CR, Mackay CR*, Vinuesa CG* (2009) Transcriptional repressor Bcl-6 directs Tfh lineage commitment. Immunity 31(3), 457-68
Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG, Giles KM, Leedman PJ, Huttloff A, Lam KP, Goodnow C*, Vinuesa CG*. (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299-303.