Halliday, Neil Alastair; (2019) CD4 regulatory T cells: their requirement for CD80 and CD86 costimulation and their role in autoimmune hepatitis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

T cell activation requires a costimulation signal, which is typically provided by CD28 binding to CD80 or CD86; hence CD80/CD86 availability is tightly regulated, in part through their removal from APCs by Treg CTLA4-dependent transendocytosis. We aimed to model the impact of changes in CD80/CD86 availability upon T cell proliferation and phenotype and to validate a quantitative assay of transendocytosis, to explore the regulation of this process. Finally, we aimed to explore the role of Treg, CTLA4 and CD80/CD86 in autoimmune hepatitis (AIH). // We demonstrated that Treg proliferation and phenotype were more sensitive to CD86 than to CD80. Although CD80 and CD86 are often considered interchangeable, we observed greater Treg proliferation, CTLA4, ICOS, and OX40 expression and reduced IL2 requirements, akin to stronger CD28 signals, following costimulation with CD86. We demonstrated that CTLA4 impaired Treg costimulation by CD80, potentially explaining why CD86 was a more effective ligand for CD28 despite its lower affinity. This suggested that the two ligands have differing roles in Treg homeostasis. // We also established an assay to quantitatively measure Treg transendocytosis of CD80, which reflected clinically significant CTLA4 mutations, and we demonstrated that IL2 and IL10 positively regulate transendocytosis. // The liver has a high degree of immunological tolerance, but when this breaks down autoimmunity can occur. We observed that the regulated immune microenvironment in the liver might be highly Treg/CTLA4-dependent and that in AIH there was an imbalance in CD80 and CD86 control, despite maintained Treg frequency and function. // In summary, we present evidence for a fundamentally different role for CD80 and CD86 in Treg homeostasis and a tool to quantitatively measure Treg transendocytosis, We present some of the 1st functional data from intrahepatic Treg in AIH and evidence of an imbalance in the control of CD28 costimulation, suggesting this pathway as a potential therapeutic target.

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