Investigating the regulation of Th17 cell fate and function at mucosal surfaces

Matei-Rascu, Veronika (2022). Investigating the regulation of Th17 cell fate and function at mucosal surfaces. University of Birmingham. Ph.D.

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Abstract

T helper 17 cells, characterised by interleukin-17 production, are crucial to appropriate mucosal immunity but, when dysregulated, are known causative agents of a multitude of inflammatory disorders. Thus, Th17 cell regulation is highly relevant to human health. However, the design and development of therapies targeted at the modulation of Th17 cell responses is impeded by gaps in the available understanding of the control of Th17 cell function and fates and a paucity of experimental systems appropriate for the comprehensive study of mucosal immune responses. Here, I took multiple interconnected approaches to begin to address some of the outstanding questions regarding mucosal Th17 cell regulation including the extent to which CD4 T cell subsets of the mucosal compartment transdifferentiate into one another, the role of costimulation and transcriptional networks in the control of these processes, and the effects of Th17 cell plasticity on memory formation. Throughout this thesis I have shown that Th17 cells do not maintain their characteristic cytokine profile but instead readily transdifferentiate into both suppressive Treg and proinflammatory Th1-like cells. By assessing the transcriptional regulation of Th17 cell function using animal models I show that three key lineage-defining transcription factor networks are integrated to control Th1-like exTh17 cell differentiation. Through characterisation of these models I show that Th17 cell effector functions, as well as development, are supported by the transcription factors RORγt and RORα. Conversely, T-bet expression within Th17 cells was found to be indispensable for complete loss of Th17 cell-associated functions but, strikingly, not for the acquisition of Th1 cell characteristics. Furthermore, I show that these novel models enable segmentation of exTh17 cell differentiation into better-defined stages, thus aiding detailed studies of this process. Moreover, I present initial characterisation of an exciting new experimental model that enables the identification and long-term tracking of CD4 T cells responding to mucosal infections, including memory T cells. Collectively these data reveal new insight into transcriptional control of Th17 cell differentiation and establish a robust experimental platform for investigating Th17 cell fate and memory formation.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):