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Mechanisms of Regulatory T Cell Migration in Dermal Inflammation
Version 2 2016-12-19, 01:21
Version 1 2016-12-19, 01:05
thesis
posted on 2016-12-19, 01:21 authored by Zachary Jing Shen ChowCritical to the
adaptive immune response, T cells have been implicated in the aetiology of
inflammatory skin diseases such as dermatitis and psoriasis. Within the T cell
population however, there exists a minor subset of T cells whose function is to
restrict inflammation. These specialised T cells are termed regulatory T cells.
Regulatory T cells exert their function via a myriad of mechanisms which include
cytokine secretion and contact-dependent suppression. Studies have shown that
the ability to localise to the site of inflammation is vital to their
regulatory function. Despite this, little is known about the behaviour of
endogenous regulatory T cells within inflamed tissues. Therefore, the aim of
this project was to investigate regulatory T cell behaviour in steady state and
inflamed skin, using the mouse model of contact sensitivity. To visualise this
behaviour, in vivo multiphoton microscopy was employed to image endogenous
regulatory T cells that were fluorescently tagged transgenically.
The experiments described in Chapter 3 characterised the migratory behaviour of regulatory T cells in the dermis. These experiments revealed that regulatory T cells were constitutively present in the dermis, with a mostly immotile behaviour in contrast to conventional CD4+ T cells. Initiation of an inflammatory response by contact sensitivity increased regulatory T cell abundance as well as the proportion of migratory regulatory T cells. This response was dependent on re-exposure to the sensitising hapten and effector cell recruitment, highlighting a role for T cell-dependent inflammation. Moreover, the increased regulatory T cell migration observed was dependent on the chemokine receptor CCR4.
Experiments in Chapter 4 further investigated the molecular basis of this increased regulatory T cell migration. These experiments demonstrated that alpha-V integrin and the PI3K subunit p110-delta also contributed to regulatory T cell migration. The role of alpha-E integrin, a molecule shown to be important for regulatory T cell retention in the skin was also investigated. However, no effect was observed following its inhibition. The findings from Chapter 4 indicate that alpha-V integrin and TCR signalling play a role in induction of regulatory T cell migration.
Studies in other organs have shown that regulatory T cells exert their regulatory function via cell contact with antigen-presenting cells. In Chapter 5, the interactions between regulatory T cells and dermal dendritic cells were investigated. The experiments revealed that interactions occur under both uninflamed and inflamed conditions, and that the duration of these interactions was reduced under inflamed conditions. Moreover, analysis of interacting cells suggested that increased regulatory T cell migration does not influence the chances of interactions with dermal dendritic cells.
Together, these findings are the first to describe endogenous regulatory T cell behaviour in steady state or inflamed skin and to characterise the molecular basis of their migration. These experiments raise the possibility that intradermal migration of regulatory T cells is important in regulation of inflammation. Moreover, they identify molecular pathways in regulatory T cells that can be used to test this hypothesis in the future.
The experiments described in Chapter 3 characterised the migratory behaviour of regulatory T cells in the dermis. These experiments revealed that regulatory T cells were constitutively present in the dermis, with a mostly immotile behaviour in contrast to conventional CD4+ T cells. Initiation of an inflammatory response by contact sensitivity increased regulatory T cell abundance as well as the proportion of migratory regulatory T cells. This response was dependent on re-exposure to the sensitising hapten and effector cell recruitment, highlighting a role for T cell-dependent inflammation. Moreover, the increased regulatory T cell migration observed was dependent on the chemokine receptor CCR4.
Experiments in Chapter 4 further investigated the molecular basis of this increased regulatory T cell migration. These experiments demonstrated that alpha-V integrin and the PI3K subunit p110-delta also contributed to regulatory T cell migration. The role of alpha-E integrin, a molecule shown to be important for regulatory T cell retention in the skin was also investigated. However, no effect was observed following its inhibition. The findings from Chapter 4 indicate that alpha-V integrin and TCR signalling play a role in induction of regulatory T cell migration.
Studies in other organs have shown that regulatory T cells exert their regulatory function via cell contact with antigen-presenting cells. In Chapter 5, the interactions between regulatory T cells and dermal dendritic cells were investigated. The experiments revealed that interactions occur under both uninflamed and inflamed conditions, and that the duration of these interactions was reduced under inflamed conditions. Moreover, analysis of interacting cells suggested that increased regulatory T cell migration does not influence the chances of interactions with dermal dendritic cells.
Together, these findings are the first to describe endogenous regulatory T cell behaviour in steady state or inflamed skin and to characterise the molecular basis of their migration. These experiments raise the possibility that intradermal migration of regulatory T cells is important in regulation of inflammation. Moreover, they identify molecular pathways in regulatory T cells that can be used to test this hypothesis in the future.
