Show simple item record

dc.contributor.advisorKuchroo, Vijay K.
dc.contributor.authorZhang, Huiyuan
dc.date.accessioned2022-03-18T04:13:30Z
dash.embargo.terms2024-03-17
dc.date.created2022
dc.date.issued2022-03-17
dc.date.submitted2022-03
dc.identifier.citationZhang, Huiyuan. 2021. IL-27-driven immunoregulatory pathways in T cells. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.
dc.identifier.other28962732
dc.identifier.urihttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371124*
dc.description.abstractIL-27 is a pleiotropic cytokine that exert immunoregulatory functions through multiple mechanisms, including induction of IL-10 and multiple co-inhibitory receptors on T cells, but the transcriptional network mediating its diverse functions remains unclear. Combining high-resolution temporal RNA profiling with computational algorithms, we predicted 79 transcription factors induced by IL-27 in T cells. We genetically perturbed 24 TFs and generated an experimentally refined regulatory network for Il10. Our study validated 11 known and discovered 5 positive (Cebpb, Fosl2, Tbx21, Hlx, Atf3) and 2 negative (Irf9, Irf8) Il10 regulators. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in Type 1 regulatory T cells, mediate IL-10 expression in other helper T cells and determine the regulatory phenotype of colonic Foxp3+ regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying the Il10-deficient mice. Our work provides insights into IL-27 driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets. In addition, using the IL-27-induced co-inhibitory gene module as a tool, we discovered LILRB4 as a new co-inhibitory receptor for cancer immunotherapy. Lilrb4-deficient mice are better at controlling tumor growth with improved effector T cell functions in the tumor microenvironment. Transferring Lilrb4-deficient Tregs partially recapitulates the tumor growth control observed in Lilrb4-deficient mice, indicating a Treg-cell intrinsic role of LILRB4 in regulating tumor growth. Moreover, we showed that LILRB4 is preferentially expressed by pathogenic Th17 cells compared to non-pathogenic homeostatic Th17 cells. LILRB4 restrains the encephalitogenicity of Th17 cells in experimental autoimmune encephalomyelitis. Our work demonstrates LILRB4 as a co-inhibitory receptor on T cell that has important function in both cancer and autoimmunity. In summary, our studies provide insights on how IL-27 suppresses autoimmunity and anti-tumor immunity by regulating IL-10 production and expression of known and novel co-inhibitory molecules such as LILRB4 in T cells.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectImmunology
dc.titleIL-27-driven immunoregulatory pathways in T cells
dc.typeThesis or Dissertation
dash.depositing.authorZhang, Huiyuan
dash.embargo.until2024-03-17
dc.date.available2022-03-18T04:13:30Z
thesis.degree.date2021
thesis.degree.grantorHarvard University Graduate School of Arts and Sciences
thesis.degree.levelDoctoral
thesis.degree.namePh.D.
dc.type.materialtext
thesis.degree.departmentMedical Sciences
dc.identifier.orcid0000-0003-0763-6856
dash.author.emailhuiyuan91@gmail.com


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record