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Type: Thesis
Title: Chemokine-mediated control of immunity to tumours and infectious pathogens
Author: Whyte, Carly Ellyse
Issue Date: 2018
School/Discipline: School of Biological Sciences
Abstract: The ability of immune cells to migrate to distinct niches and peripheral sites is critical for their appropriate differentiation and for execution of their effector functions. This migration is facilitated to a large degree by the expression of chemokine receptors, which allow for migration in a spatiotemporally-controlled manner. The work presented in this thesis addresses two distinct issues regarding how regulation of immune cell migration affects development of anti-tumour immunity and infectious immunity. In the first part of this thesis, a novel role for the atypical chemokine receptor ACKR4 in controlling anti-tumour immune responses was identified. As a scavenging receptor, ACKR4 regulates the bioavailability of the CCR7 ligands, CCL19 and CCL21, and the CCR9 ligand, CCL25. These ligands have previously been shown to be critical for many aspects of immune homeostasis, as well as contributing to tumour cell growth and metastasis. However, the contribution of ACKR4 in regulating tumour-specific responses has been unclear. Using multiple orthotopic, transgenic and chemically-induced models of cancer, loss of ACKR4 resulted in inhibited tumour growth. In the absence of ACKR4, enhanced CCL21 levels were associated with enhanced tumour infiltration of IFNy+ CD8+ T cells. The reduced tumour growth seen was dependent on the enhanced CD8+ response, with depletion of CD8+ T cells restoring growth of Ackr4–/– tumours to wildtype levels. The enhanced CD8+ T cell response was not a result of altered priming in draining lymph nodes, although there was increased intratumoural proliferation of CD8+ T cells. Furthermore, ACKR4-deficient tumours showed increased retention of CD103+ DCs, with these cells previously being shown to be critical for effective recruitment of CD8+ T cells to tumours. Moreover, intratumoural administration of CCL21 into wildtype tumours also enhanced the accumulation of DCs, suggesting a direct role for the scavenging ability of ACKR4. These data support the notion that ACKR4, through its regulation of CCL21 bioavailability, controls DC migration in tumours thus regulating the development of anti-tumour immune responses. Furthermore, multiple immunotherapies show increased efficacy in the absence of ACKR4, suggesting ACKR4 may be useful as a potential novel target for immunotherapy. In the second part of this thesis, the role of CCR2 on memory CD4+ T cells was explored. Relatively little is understood about the generation, maintenance and effector functions of memory CD4+ T cells, despite correlations with improved disease outcomes. Furthermore, how these cells migrate to inflammatory sites is still largely unknown. In this project, CCR2 was identified as being enriched on antigen-specific memory CD4+ T cells in response to infection with the extracellular bacteria Streptococcus pneumoniae and infection with influenza A virus. Competitive co-transfer of wildtype and CCR2- deficient TCR-transgenic CD4+ T cells showed enhanced contraction of Ccr2–/– cells, suggesting a cell-intrinsic role for CCR2 in CD4+ T cell maintenance. CCR2-deficient effector cells were unaffected in their ability to secrete cytokines or enter into effector sites. Moreover, despite being numerically reduced at memory timepoints compared with CCR2-sufficent cells, they were equally capable of expanding upon secondary challenge. These data highlight CCR2 as an important regulator of CD4+ T cell memory maintenance. Taken together, this project has furthered our understanding of the complexity of cell migration in dictating immune responses. The identification of CCR2 as a mediator of memory CD4+ T cell generation may allow further investigation into how these cells are induced and maintained. In ACKR4, a novel level of post-transcriptional regulation of intratumoural DC trafficking has been identified, with this having the potential to be a tractable target for therapeutic manipulation in malignant disease.
Advisor: McColl, Shaun
Comerford, Iain
Smyth, Mark
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2018
Keywords: Immunology
Streptococcus pneumonaie
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
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