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Regulation of the CD4+ T cell response to influenza infection

University of British Columbia

Surviving influenza infection requires a balance of pro- and anti- inflammatory signals, to promote viral clearance while preventing immunopathology. CD4+ T cells are central to this balance, exerting positive and negative influences on the immune response to infection. Since dysregulated CD4+ T cell responses are detrimental to survival, understanding the mechanisms controlling CD4+ T cell function during infection is essential. This thesis examines two aspects of CD4+ T cell regulation, the effect of the immunoregulatory cytokine IL-27 on CD4+ T cell function and the epigenetic control of the CD4+ T cell response to influenza. In chapter 3, I show that IL-27 signalling can regulate the immune response to influenza by inducing IL-10 from effector CD4+ T cells in primary and recall infection. Since regulated IL-10 expression is important for a protective Th1 response, I investigated the mechanism through which IL-27 promotes CD4+ T cell derived IL-10. I found that IL-27 signalling enhances IL-10 expression from effector CD4+ T cells in a primary response but memory cells lose their responsiveness to IL-27. However, these memory cells re-express IL-10 in a recall response to influenza due to an IL-27 induced permissive epigenetic signature deposited at the Il10 locus during primary activation. In chapter 4, I investigated the effect of IL-27 on functional specialisation in Tregs during infection. Upon exposure to IL-27, airway Tregs exhibited a Th1 adapted phenotype characterised by increased T-bet, CXCR3 and IL-10 expression. In Chapter 5, I investigated the link between histone modifications and gene-expression in naïve, effector and memory CD4+ T cells. I found that dynamic changes in histone modifications at gene promoters are associated with temporal gene expression patterns and that super-enhancer target genes encode highly expressed lineage specific determinants in naïve and effector cells. I also show that memory cells contain a subset of primed effector genes and re-express key genes specifying naïve cell identity. Collectively, my findings indicate that IL-27 regulates effector CD4+ and Treg cell function in the lung and that the control of gene expression in effector and memory CD4+ T cells can be achieved through epigenetic modifications at promoter and super-enhancer elements.

Text

2021-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/70044

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/